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1
Nguyen, Taitan, Neal A. Rubinstein, Camasamudram Vijayasarathy, Lawrence C. Rome, Larry R. Kaiser, Joseph B. Shrager, and Sanford Levine. "Effect of chronic obstructive pulmonary disease on calcium pump ATPase expression in human diaphragm." Journal of Applied Physiology 98, no. 6 (June 2005): 2004–10. http://dx.doi.org/10.1152/japplphysiol.00767.2004.
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We have previously demonstrated that human diaphragm remodeling elicited by severe chronic obstructive pulmonary disease (COPD) is characterized by a fast-to-slow myosin heavy chain isoform transformation. To test the hypothesis that COPD-induced diaphragm remodeling also elicits a fast-to-slow isoform shift in the sarcoendoplasmic reticulum Ca2+ ATPase (SERCA), the other major ATPase in skeletal muscle, we obtained intraoperative biopsies of the costal diaphragm from 10 severe COPD patients and 10 control subjects. We then used isoform-specific monoclonal antibodies to characterize diaphragm fibers with respect to the expression of SERCA isoforms. Compared with control diaphragms, COPD diaphragms exhibited a 63% decrease in fibers expressing only fast SERCA (i.e., SERCA1; P < 0.001), a 190% increase in fibers containing both fast and slow SERCA isoforms ( P < 0.01), and a 19% increase ( P < 0.05) in fibers expressing only the slow SERCA isoform (i.e., SERCA2). Additionally, immunoblot experiments carried out on diaphragm homogenates indicated that COPD diaphragms expressed only one-third the SERCA1 content noted in control diaphragms; in contrast, COPD and control diaphragms did not differ with respect to SERCA2 content. The combination of these histological and immunoblot results is consistent with the hypothesis that diaphragm remodeling elicited by severe COPD is characterized by a fast-to-slow SERCA isoform transformation. Moreover, the combination of these SERCA data and our previously reported myosin heavy chain isoform data (Levine S, Nguyen T, Kaiser LR, Rubinstein NA, Maislin G, Gregory C, Rome LC, Dudley GA, Sieck GC, and Shrager JB. Am J Respir Crit Care Med 168: 706–713, 2003) suggests that diaphragm remodeling elicited by severe COPD should decrease ATP utilization by the diaphragm.
2
Farkas, G. A., and D. F. Rochester. "Functional characteristics of canine costal and crural diaphragm." Journal of Applied Physiology 65, no. 5 (November 1, 1988): 2253–60. http://dx.doi.org/10.1152/jappl.1988.65.5.2253.
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We estimated the in situ force-generating capacity of the costal and crural portions of the canine diaphragm by relating in vitro contractile properties and diaphragmatic dimensions to in situ lengths. Piezoelectric crystals were implanted on right costal and left crural diaphragms of anesthetized dogs, via midline laparatomy. With the abdomen reclosed, diaphragm lengths were recorded at five lung volumes. Contractile properties of excised muscle bundles were then measured. In vitro force-frequency and length-tension characteristics of the costal and crural diaphragms were virtually identical; their optimal force values were 2.15 and 2.22 kg/cm2, respectively. In situ, at residual volume, functional residual capacity (FRC), and total lung capacity the costal diaphragm lay at 102, 95, and 60% of optimal length (Lo), whereas the crural diaphragm lay at 88, 84, and 66% of Lo. Muscle cross-sectional area was 40% greater in costal than in crural diaphragms. Considering in situ lengths, cross-sectional areas, and in vitro length-tension characteristics at FRC, the costal diaphragm could exert 60% more force than the crural diaphragm.
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Bazzy, A. R. "Effect of hypoxia on neuromuscular transmission in the developing diaphragm." Journal of Applied Physiology 76, no. 2 (February 1, 1994): 708–13. http://dx.doi.org/10.1152/jappl.1994.76.2.708.
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To study the effects of hypoxia on neuromuscular transmission in the developing diaphragm, phrenic nerve-hemidiaphragm preparations were obtained from newborn (4–9 days) and older (22–30 days) rats. Diaphragms were stimulated directly or indirectly (via the nerve) for 1 s at frequencies of 10–80 Hz. Force generated in response to stimulation was measured during perfusion of oxygenated Ringer solution (control) and Ringer solution bubbled with 95% N2–5% CO2 (hypoxia). After 45 min of hypoxia, the force response of the older diaphragms to direct stimulation had decreased to approximately 50% of control at > or = 40 Hz; however, when stimulation occurred via the nerve at these frequencies only 15–20% of control force was generated. In the newborn diaphragms, the force decrement after similar or longer periods of hypoxia (< or = 90 min) was 30– 40% irrespective of the route or frequency of stimulation. After 15 min of reoxygenation, the force response to both muscle and nerve stimulation recovered completely in the older diaphragms but only partially in the newborn diaphragms (range 77% of control at 50 Hz to 95% of control at 10 Hz). These data suggest that in the newborn diaphragm 1) neuromuscular transmission is more resistant to the effects of hypoxia than the older diaphragm and 2) the predominant effect of hypoxia is peripheral in the diaphragm muscle fibers, whereas in the older diaphragm the effect is before or at the neuromuscular junction.
4
Margulies, S. S. "Regional variation in canine diaphragm thickness." Journal of Applied Physiology 70, no. 6 (June 1, 1991): 2663–68. http://dx.doi.org/10.1152/jappl.1991.70.6.2663.
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To quantify the relationship between both regional and overall diaphragm morphometry and body weight in the dog, diaphragm thickness was measured in five regions of the costal diaphragm and three regions of the crural diaphragm in 40 healthy dogs (8-40 kg). Surface area of the diaphragm, diaphragm weight, and body weight were also determined. Diaphragm surface area and weight varied linearly with body weight, but there was no significant correlation between overall diaphragm thickness and body weight. Diaphragm thickness varied significantly between regions, and three regions had systematic left-to-right differences as well. Because diaphragm geometry influences the diaphragm's function as a pressure generator, regional differences in thickness may alter the relationship between the force developed by the activation of a particular region of the diaphragm and its action on the respiratory system.
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Sugiura, T., S. Morita, A. Morimoto, and N. Murakami. "Regional differences in myosin heavy chain isoforms and enzyme activities of the rat diaphragm." Journal of Applied Physiology 73, no. 2 (August 1, 1992): 506–9. http://dx.doi.org/10.1152/jappl.1992.73.2.506.
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Myosin heavy chain isoforms and enzyme activities were compared between the costal and crural regions of the rat diaphragm. The percentage of heavy chain (HC) IIb in the crural region of the diaphragm was significantly (P less than 0.05) higher than that in the costal region (mean 7.3 vs. 3.0%), and the percentage of HCI was significantly lower in the crural than in the costal diaphragm (22.7 vs. 27.9%). The distributions of HCIIa and HCIId were relatively homogeneous in both regions. Succinate dehydrogenase activity in the costal diaphragm was 21% greater (P less than 0.01) than in the crural diaphragm. In contrast, there was no significant difference in the activity of phosphofructokinase in the crural and costal diaphragms. These results demonstrate that a difference in myosin heavy chain isoforms and oxidative capacity exists between the costal and crural regions of the rat diaphragm.
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Lewis, M. I., W. Z. Zhan, and G. C. Sieck. "Adaptations of the diaphragm in emphysema." Journal of Applied Physiology 72, no. 3 (March 1, 1992): 934–43. http://dx.doi.org/10.1152/jappl.1992.72.3.934.
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In adult male hamsters the influence of emphysema (EMP) on the in vitro contractile and fatigue properties and the histochemical, morphometric, and metabolic properties of muscle fibers in the costal diaphragm was determined 6 mo after the administration of either elastase or saline (controls, CTL). Isometric contractile properties were determined in vitro using supramaximal direct muscle stimulation. Optimal fiber length for force generation was significantly shorter in the EMP than in the CTL diaphragm. Maximum specific force (i.e., force per unit area) was 25% lower than CTL. Fatigue resistance was significantly improved in the EMP diaphragm compared with CTL. Diaphragm muscle fibers were classified as type I or II on the basis of histochemical staining for myofibrillar adenosinetriphosphatase after alkaline preincubation. The proportions of type I and II fibers were similar between the two groups. Cross-sectional areas of type II fibers were 30% larger in EMP than in CTL diaphragms. Succinate dehydrogenase activities of both type I and II fibers were higher in EMP than in CTL diaphragms. The number of capillaries surrounding both type I and II fibers increased with EMP, but in proportion to the hypertrophy of these fibers. Thus, capillary density (number of capillaries per fiber cross-sectional area) remained unchanged. We postulate that these contractile, morphometric, and metabolic adaptations reflect an increased activation of the diaphragm in response to the loads imposed by EMP.
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Matecki, Stefan, Ghiabe H. Guibinga, and Basil J. Petrof. "Regenerative capacity of the dystrophic (mdx) diaphragm after induced injury." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 287, no. 4 (October 2004): R961—R968. http://dx.doi.org/10.1152/ajpregu.00146.2004.
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Duchenne muscular dystrophy is characterized by myofiber necrosis, muscle replacement by connective tissue, and crippling weakness. Although the mdx mouse also lacks dystrophin, most muscles show little myofiber loss or functional impairment. An exception is the mdx diaphragm, which is phenotypically similar to the human disease. Here we tested the hypothesis that the mdx diaphragm has a defective regenerative response to necrotic injury, which could account for its severe phenotype. Massive necrosis was induced in mdx and wild-type (C57BL10) mouse diaphragms in vivo by topical application of notexin, which destroys mature myofibers while leaving myogenic precursor satellite cells intact. At 4 h after acute exposure to notexin, >90% of diaphragm myofibers in both wild-type and mdx mice demonstrated pathological sarcolemmal leakiness, and there was a complete loss of isometric force-generating capacity. Both groups of mice showed strong expression of embryonic myosin within the diaphragm at 5 days, which was largely extinguished by 20 days after injury. At 60 days postinjury, wild-type diaphragms exhibited a persistent loss (∼25%) of isometric force-generating capacity, associated with a trend toward increased connective tissue infiltration. In contrast, mdx diaphragms achieved complete functional recovery of force generation to noninjured values, and there was no increase in muscle connective tissue over baseline. These data argue against any loss of intrinsic regenerative capacity within the mdx diaphragm, despite characteristic features of major dystrophic pathology being present. Our findings support the concept that significant latent regenerative capacity resides within dystrophic muscles, which could potentially be exploited for therapeutic purposes.
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Supinski, Gerald S., and Leigh A. Callahan. "Diaphragmatic free radical generation increases in an animal model of heart failure." Journal of Applied Physiology 99, no. 3 (September 2005): 1078–84. http://dx.doi.org/10.1152/japplphysiol.01145.2004.
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Heart failure evokes diaphragm weakness, but the mechanism(s) by which this occurs are not known. We postulated that heart failure increases diaphragm free radical generation and that free radicals trigger diaphragm dysfunction in this condition. The purpose of the present study was to test this hypothesis. Experiments were performed using halothane-anesthetized sham-operated control rats and rats in which myocardial infarction was induced by ligation of the left anterior descending coronary artery. Animals were killed 6 wk after surgery, the diaphragms were removed, and the following were assessed: 1) mitochondrial hydrogen peroxide (H2O2) generation, 2) free radical generation in resting and contracting intact diaphragm using a fluorescent-indicator technique, 3) 8-isoprostane and protein carbonyls (indexes of free radical-induced lipid and protein oxidation), and 4) the diaphragm force-frequency relationship. In additional experiments, a group of coronary ligation animals were treated with polyethylene glycol-superoxide dismutase (PEG-SOD, 2,000 units·kg−1·day−1) for 4 wk. We found that coronary ligation evoked an increase in free radical formation by the intact diaphragm, increased diaphragm mitochondrial H2O2 generation, increased diaphragm protein carbonyl levels, and increased diaphragm 8-isoprostane levels compared with controls ( P < 0.001 for the first 3 comparisons, P < 0.05 for 8-isoprostane levels). Force generated in response to 20-Hz stimulation was reduced by coronary ligation ( P < 0.05); PEG-SOD administration restored force to control levels ( P < 0.03). These findings indicate that cardiac dysfunction due to coronary ligation increases diaphragm free radical generation and that free radicals evoke reductions in diaphragm force generation.
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Lewis, M. I., G. C. Sieck, M. Fournier, and M. J. Belman. "Effect of nutritional deprivation on diaphragm contractility and muscle fiber size." Journal of Applied Physiology 60, no. 2 (February 1, 1986): 596–603. http://dx.doi.org/10.1152/jappl.1986.60.2.596.
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The influence of nutritional deprivation on the contractile and fatigue properties of the diaphragm was studied in adult rats. Food access was restricted to one-third of normal daily intake until the body weight of nutritionally deprived (ND) animals was approximately 50% of controls (CTL). Isometric contractile properties were studied in an in vitro nerve muscle strip preparation. Both twitch (Pt) and tetanic (Po) tensions of diaphragms from the ND animals were markedly reduced compared with CTL; however, Pt/Po was higher for the ND group. The shape of the force-frequency curve (normalized to Po) was generally similar between the two groups, except at 5 and 10 pulses/s stimulation, where greater relative tensions were produced in diaphragms from the ND animals. Diaphragm fatigue was induced by repetitive stimulation at either 20 or 100 pulses/s. Endurance time (defined as the time required for tension to fall to 50% of initial) of diaphragms from ND animals was prolonged at both 20 and 100 pulses/s. Immediately after induction of fatigue, force-frequency curves for both ND and CTL diaphragms were shifted to the right. However, this rightward shift was attenuated in the ND group compared with CTL. Nutritional deprivation had no effect on the proportions of different fiber types within the diaphragm but did result in a significant decrease in the cross-sectional area of both fast-and slow-twitch fibers. This decrease in cross-sectional area was significantly greater for fast-twitch fibers. We conclude that these changes in diaphragm contractile and fatigue properties occur as a result of the influence of malnutrition on muscle fiber cross-sectional area.
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Stan, Radu V. "Multiple PV1 dimers reside in the same stomatal or fenestral diaphragm." American Journal of Physiology-Heart and Circulatory Physiology 286, no. 4 (April 2004): H1347—H1353. http://dx.doi.org/10.1152/ajpheart.00909.2003.
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Several of the endothelium-specific structures that have been involved in microvascular permeability [such as caveolae, transendothelial channels (TECs), vesiculovacuolar organelles (VVOs), and fenestrae] can be provided with either a stomatal or fenestral diaphragm. In the case of fenestrae, the diaphragm has the presumed function of creating a permselective barrier for solutes from blood plasma and interstitium. PV1 is an endothelium-specific integral membrane glycoprotein that is associated with both the stomatal diaphragms of caveolae, TECs, and VVOs as well as the diaphragms of endothelial fenestrae. The intimate structure of these diaphragms has been shown to consist of a meshwork formed by radial fibrils. We have recently shown that PV1 is a key structural element of both types of diaphragms, with its expression being sufficient to form de novo stomatal and fenestral diaphragms in both endothelial and nonendothelial cell types in culture. We have further tested the role of PV1 in the structure of the diaphragms and demonstrate here that multiple PV1 homodimers reside in close proximity within the same diaphragm. Our data bring further support to the paradigm by which PV1 dimers would form the fibrils of the diaphragms with a function in the microvascular permeability.
11
Poole, David C., and Odile Mathieu-Costello. "Effect of pulmonary emphysema on diaphragm capillary geometry." Journal of Applied Physiology 82, no. 2 (February 1, 1997): 599–606. http://dx.doi.org/10.1152/jappl.1997.82.2.599.
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Poole, David C., and Odile Mathieu-Costello. Effect of pulmonary emphysema on diaphragm capillary geometry. J. Appl. Physiol. 82(2): 599–606, 1997.—In emphysema, the diaphragm shortens by losing sarcomeres. We hypothesized that unless capillaries undergo a similar shortening, capillary geometry must be altered. Without quantifying this geometry, capillary length and surface area per fiber volume, which are critical measurements of the structural potential for blood-tissue exchange, cannot be resolved. Five months after intratracheal elastase (E) or saline (control; C) instillation, diaphragms from male Syrian golden hamsters were glutaraldehyde perfusion fixed in situ at reference lung positions (residual volume, functional residual capacity, total lung capacity) to provide diaphragms fixed over a range of sarcomere lengths. Subsequently, diaphragms were processed for electron microscopy and analyzed morphometrically. Emphysema increased lung volume changes from −20 to 25 cmH2O airway pressure (i.e., passive vital capacity) and excised lung volume (both P < 0.001). In each region of the costal diaphragm (i.e., ventral, medial, dorsal), sarcomere number was reduced (all P < 0.05). Capillary-to-fiber ratio increased (C = 2.2 ± 0.1, E = 2.8 ± 0.1; P < 0.01) and fibers hypertrophied (C = 815 ± 35, E = 987 ± 67 μm2; P < 0.05; both values at 2.5 μm sarcomere length). Capillary geometry was markedly altered by the loss of sarcomeres in series. Specifically, the additional capillary length derived from capillary tortuosity and branching was increased by 183% at 2.5 μm sarcomere length compared with C values (C, 359 ± 43; E, 1,020 ± 158 mm−2, P < 0.01). This significantly increased total capillary length (C, 3,115 ± 173; E, 3,851 ± 219 mm−2 at 2.5 μm, P < 0.05) and surface area (C, 456 ± 13; E, 519 ± 24 cm−1, P < 0.05) per fiber volume. Thus emphysema substantially alters diaphragm capillary geometry and augments the capillary length and surface area available for blood-tissue exchange.
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Supinski, G. S., W. Wang, and L. A. Callahan. "Caspase and calpain activation both contribute to sepsis-induced diaphragmatic weakness." Journal of Applied Physiology 107, no. 5 (November 2009): 1389–96. http://dx.doi.org/10.1152/japplphysiol.00341.2009.
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The cecal ligation perforation (CLP) model of sepsis is known to induce severe diaphragm dysfunction, but the cellular mechanisms by which this occurs remain unknown. We hypothesized that CLP induces diaphragm caspase-3 and calpain activation, and that these two enzymes act at the level of the contractile proteins to reduce muscle force generation. Rats ( n = 4/group) were subjected to 1) sham surgery plus saline (intraperitoneal); 2) CLP; 3) CLP plus administration of calpain inhibitor peptide III (12 mg/kg ip); or 4) CLP plus administration of a caspase inhibitor, zVAD-fmk (3 mg/kg). At 24 h, diaphragms were removed, and the following were determined: 1) calpain and caspase-3 activities by fluorogenic assay; 2) caspase-3 and calpain I protein levels; 3) the intact diaphragm force-frequency relationship; and 4) the force generated by contractile proteins of single, permeabilized diaphragm fibers in response to exogenous calcium. CLP significantly increased diaphragm calpain activity ( P < 0.02), caspase-3 activity ( P < 0.02), active calpain I protein levels ( P < 0.02), and active caspase-3 protein ( P < 0.02). CLP also reduced the force generated by intact diaphragm muscle ( P < 0.001) and the force generated by single-fiber contractile proteins ( P < 0.001). Administration of either calpain inhibitor III or zVAD-fmk markedly improved force generation of both intact diaphragm muscle ( P < 0.01) and single-fiber contractile proteins ( P < 0.001). CLP induces significant reductions in diaphragm contractile protein force-generating capacity. This force reduction is mediated by the combined effects of activated caspase and calpain. Inhibition of these pathways may prevent diaphragm weakness in infected patients.
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Road, J., S. Newman, J. P. Derenne, and A. Grassino. "In vivo length-force relationship of canine diaphragm." Journal of Applied Physiology 60, no. 1 (January 1, 1986): 63–70. http://dx.doi.org/10.1152/jappl.1986.60.1.63.
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Diaphragmatic length was measured by sonomicrometry and transdiaphragmatic pressure (Pdi) by conventional latex balloons in eight dogs anesthetized with pentobarbital sodium under passive conditions and during supramaximal phrenic stimulation. The passive length-pressure relationship indicates that the crural part of the diaphragm is more compliant than the costal part. With supramaximal stimulation the costal diaphragm showed a length-pressure relationship similar in shape to in vitro length-tension curves previously described for the canine diaphragm. The crural part has a smaller pressure-length slope than the costal part in the length range from 80% of optimum muscle length (Lo) to Lo. At supine functional residual capacity (FRC) the resting length (LFRC) of the costal and crural diaphragms are not at Lo. The costal part is distended to 105% of Lo, and crural is shortened to 92% of Lo. Tidal shortening will increase the force output of costal while decreasing that of the crural diaphragm. The major forces setting the passive supine LFRC are the abdominal weight (pressure) and the elastic recoil of the lungs. The equilibrium length (resting length of excised diaphragmatic strips) was 79 +/- 3.6% LFRC for the costal diaphragm and 87 +/- 3.9% LFRC for the crural diaphragm. Similar shortening was obtained in the upright position, indicating passive diaphragmatic stretch at supine LFRC.
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Supinski, G., D. Nethery, D. Stofan, W. Hirschfield, and A. DiMarco. "Diaphragmatic lipid peroxidation in chronically loaded rats." Journal of Applied Physiology 86, no. 2 (February 1, 1999): 651–58. http://dx.doi.org/10.1152/jappl.1999.86.2.651.
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Recent work indicates that free radical-mediated lipid peroxidation takes place within the diaphragm on strenuous contraction. This phenomenon has only been demonstrated using fairly artificial experimental models and has not been studied during the type of sustained respiratory loading typically seen in patients with lung disease. The purpose of the present study was to measure the levels of several biochemical markers of protein oxidation (protein carbonyl levels) and lipid peroxidation (8-isoprostane, reduced glutathione, and oxidized glutathione levels) in diaphragms of rats subjected to chronic respiratory loading. Respiratory loading was accomplished by tracheal banding; groups of animals were loaded for 4, 8, or 12 days, and a group of sham-operated unloaded animals was used as controls. After loading, animals were killed, diaphragm contractility was assessed in vitro by using a portion of the excised diaphragm, and the remaining diaphragm and the soleus muscles were used for biochemical analysis. We found diminished force generation in diaphragms from all groups of banded animals compared with muscles from controls. For example, twitch force averaged 7.8 ± 0.8 (SE) N/cm2 in unloaded animals and 4.0 ± 0.4, 3.0 ± 0.4, and 3.4 ± 0.4 N/cm2 in animals loaded for 4, 8, and 12 days, respectively ( P < 0.0001). Loading also elicited increases in diaphragmatic protein carbonyl concentrations ( P < 0.001), and the time course of alterations in carbonyl levels paralleled loading-induced alterations in the diaphragm force-frequency relationship. Although loading was also associated with increases in diaphragmatic 8-isoprostane levels ( P< 0.003) and reductions in diaphragm reduced glutathione levels ( P < 0.003), the time course of changes in these latter parameters did not correspond to alterations in force. Soleus glutathione and carbonyl levels were not altered by banding. We speculate that respiratory loading-induced alterations in diaphragmatic force generation may be related to free radical-mediated protein oxidation, but not to free radical-induced lipid peroxidation.
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Singh, Yadhu N., Evelyn H. Schlenker, Brahma N. Singh, and James A. Burbach. "Consequences of thyroxine treatment on diaphragm and EDL of normal and dystrophic hamsters." Canadian Journal of Physiology and Pharmacology 82, no. 5 (May 1, 2004): 345–52. http://dx.doi.org/10.1139/y04-029.
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Previously administration of thyroxine (T4) to dystrophic hamsters improved ventilation and slowed the progression of the disease. We hypothesized that the normalization of ventilation in these animals was due to T4 improving structural and functional characteristics of the diaphragm. In the present study, contractile characteristics of the diaphragm and the extensor digitorum longus (EDL) from normal and dystrophic hamsters were evaluated after two months of T4 treatment. Compared to their placebo-treated counterparts, diaphragms and EDLs of T4-treated normal hamsters showed increased optimal muscle lengths and twitch tension, decreased contraction times and increased fatigability. T4-treatment in dystrophic hamsters showed only an increase in diaphragmatic twitch tension development. Force-frequency curves before treatment were generally higher for the normal compared to dystrophic diaphragms and EDLs. T4 administration only increased the force in normal diaphragms at the lower frequencies and in the EDLs at the higher frequencies. Although T4 serum levels were increased in both T4-treated groups, triiodothyronine (T3) was much lower in the dystrophic compared to normal hamsters, suggesting that conversion of T4 to T3 was reduced in dystrophic hamsters. We conclude that the limited functional changes in the diaphragms of T4-treated dystrophic hamsters cannot account for the marked improvement in ventilation previously reported.Key words: dystrophy, thyroid hormones, skeletal muscles, diaphragm.
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Poole, David C., William L. Sexton, Bradley J. Behnke, Christine S. Ferguson, K. Sue Hageman, and Timothy I. Musch. "Respiratory muscle blood flows during physiological and chemical hyperpnea in the rat." Journal of Applied Physiology 88, no. 1 (January 1, 2000): 186–94. http://dx.doi.org/10.1152/jappl.2000.88.1.186.
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Whether the diaphragm retains a vasodilator reserve at maximal exercise is controversial. To address this issue, we measured respiratory and hindlimb muscle blood flows and vascular conductances using radiolabeled microspheres in rats running at their maximal attainable treadmill speed (96 ± 5 m/min; range 71–116 m/min) and at rest while breathing either room air or 10% O2-8% CO2 (balance N2). All hindlimb and respiratory muscle blood flows measured increased during exercise ( P < 0.001), whereas increases in blood flow while breathing 10% O2-8% CO2 were restricted to the diaphragm only. During exercise, muscle blood flow increased up to 18-fold above rest values, with the greatest mass specific flows (in ml ⋅ min−1 ⋅ 100 g−1) found in the vastus intermedius (680 ± 44), red vastus lateralis (536 ± 18), red gastrocnemius (565 ± 47), and red tibialis anterior (602 ± 44). During exercise, blood flow was higher ( P < 0.05) in the costal diaphragm (395 ± 31 ml ⋅ min−1 ⋅ 100 g−1) than in the crural diaphragm (286 ± 17 ml ⋅ min−1 ⋅ 100 g−1). During hypoxia+hypercapnia, blood flows in both the costal and crural diaphragms (550 ± 70 and 423 ± 53 ml ⋅ min−1 ⋅ 100 g−1, respectively) were elevated ( P < 0.05) above those found during maximal exercise. These data demonstrate that there is a substantial functional vasodilator reserve in the rat diaphragm at maximal exercise and that hypoxia + hypercapnia-induced hyperpnea is necessary to elevate diaphragm blood flow to a level commensurate with its high oxidative capacity.
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Callahan, Leigh A., and Gerald S. Supinski. "Diaphragm and cardiac mitochondrial creatine kinases are impaired in sepsis." Journal of Applied Physiology 102, no. 1 (January 2007): 44–53. http://dx.doi.org/10.1152/japplphysiol.01204.2005.
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Previous studies indicate that ATP formation by the electron transport chain is impaired in sepsis. However, it is not known whether sepsis affects the mitochondrial ATP transport system. We hypothesized that sepsis inactivates the mitochondrial creatine kinase (MtCK)-high energy phosphate transport system. To examine this issue, we assessed the effects of endotoxin administration on mitochondrial membrane-bound creatine kinase, an important trans-mitochondrial ATP transport system. Diaphragms and hearts were isolated from control ( n = 12) and endotoxin-treated (8 mg·kg−1·day−1; n = 13) rats after pentobarbital anesthesia. We isolated mitochondria using techniques that allow evaluation of the functional coupling of mitochondrial creatine kinase MtCK activity to oxidative phosphorylation. MtCK functional activity was established by 1) determining ATP/creatine-stimulated oxygen consumption and 2) assessing total creatine kinase activity in mitochondria using an enzyme-linked assay. We examined MtCK protein content using Western blots. Endotoxin markedly reduced diaphragm and cardiac MtCK activity, as determined both by ATP/creatine-stimulated oxygen consumption and by the enzyme-linked assay (e.g., ATP/creatine-stimulated mitochondrial respiration was 173.8 ± 7.3, 60.5 ± 9.3, 210.7 ± 18.9, was 67.9 ± 7.3 natoms O·min−1·mg−1 in diaphragm control, diaphragm septic, cardiac control, and cardiac septic samples, respectively; P < 0.001 for each tissue comparison). Endotoxin also reduced diaphragm and cardiac MtCK protein levels (e.g., protein levels declined by 39.5% in diaphragm mitochondria and by 44.2% in cardiac mitochondria; P < 0.001 and P = 0.009, respectively, comparing sepsis to control conditions). Our data indicate that endotoxin markedly impairs the MtCK-ATP transporter system; this phenomenon may have significant effects on diaphragm and cardiac function.
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Wait, J. L., D. Staworn, and D. C. Poole. "Diaphragm thickness heterogeneity at functional residual capacity and total lung capacity." Journal of Applied Physiology 78, no. 3 (March 1, 1995): 1030–36. http://dx.doi.org/10.1152/jappl.1995.78.3.1030.
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One of the determinants of muscular force is the number of myofibrils in parallel, which is approximated by thickness. To better understand the heterogeneity of diaphragm thickness, we quantified the interregional and radial patterns of thickness of nine canine diaphragms rapidly perfusion fixed in situ with glutaraldehyde at functional residual capacity (FRC) (n = 6) and total lung capacity (TLC) (n = 3). Thickness was determined gravimetrically from punch biopsies radiating from the central tendon to rib cage insertion in ventral, middle, and dorsal costal and crural regions. For comparison, the contralateral unfixed hemidiaphragm was sampled in the same fashion. The findings of this investigation include the following. 1) The costal diaphragm exhibits the same pattern of interregional heterogeneity at FRC, TLC, and in the freshly excised state. 2) The costal diaphragm is significantly thinner at FRC in situ (0.17 +/- 0.01 cm) than is the freshly excised contralateral diaphragm (0.21 +/- 0.01 cm; P < 0.05), whereas there is no significant difference between thickness at TLC and the freshly excised state. 3) There is significant, previously underscribed, radial tapering from the rib cage attachment (0.24 +/- 0.02) to the central tendon insertion (0.15 +/- 0.01 cm; P < 0.05) that is exaggerated at TLC. 4) With passive inflation from FRC to TLC, the greatest increase in thickness occurs close to the rib cage attachment for the ventral and medial costal regions but close to the central tendon in the dorsal and crural regions. We conclude that the diaphragm at FRC and TLC exhibits radial thickness heterogeneity that cannot be predicted from dimensions of the freshly excised diaphragm.(ABSTRACT TRUNCATED AT 250 WORDS)
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Le Souef, P. N., S. J. England, H. A. Stogryn, and A. C. Bryan. "Comparison of diaphragmatic fatigue in newborn and older rabbits." Journal of Applied Physiology 65, no. 3 (September 1, 1988): 1040–44. http://dx.doi.org/10.1152/jappl.1988.65.3.1040.
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The ability to maintain occlusion pressure (i.e., fatigability) during activation of the diaphragm via phrenic nerve stimulation was compared in newborn (less than 14 days old) and older (greater than 30 days old) rabbits. The younger animals had lower maximum inspiratory pressures (MIP) and markedly greater falls in pressure during sustained diaphragmatic contractions at greater than 40% MIP than did the older animals. Histological analysis showed a paucity of high-oxidative type I fibers in the diaphragms of the young animals. We therefore conclude that the newborn rabbit diaphragm is extremely susceptible to fatigue and that this susceptibility correlates with the distribution of muscle fiber types.
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Barreiro, E., J. B. Gáldiz, M. Mariñán, F. J. Alvarez, S. N. A. Hussain, and J. Gea. "Respiratory loading intensity and diaphragm oxidative stress: N-acetyl-cysteine effects." Journal of Applied Physiology 100, no. 2 (February 2006): 555–63. http://dx.doi.org/10.1152/japplphysiol.00780.2005.
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We hypothesized that resistive breathing of moderate to high intensity might increase diaphragm oxidative stress, which could be partially attenuated by antioxidants. Our objective was to assess the levels of oxidative stress in the dog diaphragm after respiratory muscle training of a wide range of intensities and whether N-acetyl-cysteine (NAC) might act as an antioxidant. Twelve Beagle dogs were anesthetized with 1% propophol, tracheostomized, and subjected to continuous inspiratory resistive breathing (IRB) (2 h/day for 2 wk). They were further divided into two groups ( n = 6): NAC group (oral NAC administration/24 h for 14 days) and control group (placebo). Diaphragm biopsies were obtained before (baseline biopsy) and after (contralateral hemidiaphragm) IRB and NAC vs. placebo treatment. Oxidative stress was evaluated in all diaphragm biopsies through determination of 3-nitrotyrosine immunoreactivity, protein carbonylation, hydroxynoneal protein adducts, Mn-SOD, and catalase, using immunoblotting and immunohistochemistry. Both protein tyrosine nitration and protein carbonylation were directly related to the amount of the respiratory loads, and NAC treatment abrogated this proportional rise in these two indexes of oxidative stress in response to increasing inspiratory loads. A post hoc analysis revealed that only the diaphragms of dogs subjected to high-intensity loads showed a significant increase in both protein tyrosine nitration and carbonylation, which were also significantly reduced by NAC treatment. These results suggest that high-intensity respiratory loading-induced oxidative stress may be neutralized by NAC treatment during IRB in the canine diaphragm.
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Derenne, J.-Ph, A. Debru, A. E. Grassino, and W. A. Whitelaw. "The earliest history of diaphragm physiology." European Respiratory Journal 7, no. 12 (December 1, 1994): 2234–40. http://dx.doi.org/10.1183/09031936.94.07122234.
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Prezant, D. J., B. Richner, D. E. Valentine, T. K. Aldrich, C. L. Fishman, H. Nagashima, I. Chaudhry, and J. Cahill. "Temperature dependence of rat diaphragm muscle contractility and fatigue." Journal of Applied Physiology 69, no. 5 (November 1, 1990): 1740–45. http://dx.doi.org/10.1152/jappl.1990.69.5.1740.
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The diaphragm is a skeletal muscle of mixed fiber type that is unique in its requirement to maintain contractile function and fatigue resistance across a wide range of temperatures to sustain alveolar ventilation under conditions of hypo- or hyperthermia. The direct effect of temperature (15-41 degrees C) on rat diaphragm isometric contractility and fatigue was determined in vitro. As temperature decreased from 37 to 15 degrees C, contraction and relaxation times increased, and there was a left shift of the diaphragm's force-frequency curve, with decreased contractility at 41 and 15 degrees C. Fatigue was induced by 10 min of stimulation with 30 trains/min of 5 Hz at a train duration of 900 ms. Compared with 37 degrees C, fatigue resistance was enhanced at 25 degrees C, but no difference in fatigue indexes was evident at extreme hypothermia (15 degrees C) or hyperthermia (41 degrees C). Only when the fatigue program was adjusted to account for hypothermia-induced increases in tension-time indexes was fatigue resistance evident at 15 degrees C. These findings indicate that despite the diaphragm's unique location as a core structure, necessitating exposure to in vivo temperatures higher than found in limb muscle, the temperature dependence of rat diaphragm muscle contractility and fatigue is similar to that reported for limb muscle of mixed fiber type.
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Hunter, E. G., and J. Elbrink. "Electrophysiological observations on diaphragm muscle from normal and dystrophic hamsters." Canadian Journal of Physiology and Pharmacology 63, no. 11 (November 1, 1985): 1474–76. http://dx.doi.org/10.1139/y85-242.
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The cellular electrical activity of diaphragm from F1B normal and BIO 14.6 dystrophic hamsters has been investigated using microelectrodes. Resting membrane potentials and action potentials were recorded from control muscles and from muscles exposed to 2,4-dinitrophenol. The action potentials of normal and dystrophic diaphragms were similar in amplitude and configuration. Treatment with 2,4-dinitrophenol caused the action potential amplitude of both diaphragms to decline by similar amounts. The control resting membrane potential of diaphragm from dystrophic hamsters is not significantly different from that of normal hamsters. Treatment with 2,4-dinitrophenol caused a linear decrease in the resting membrane potentials of both groups of muscles. Dystrophic muscle, however, showed a more rapid decline in excitability when exposed to 2,4-dinitrophenol. This suggests that adenosine triphosphate production in dystrophic muscle is partially inhibited as has been suggested by other workers.
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Teitelbaum, J. S., S. A. Magder, C. Roussos, and S. N. Hussain. "Effects of diaphragmatic ischemia on the inspiratory motor drive." Journal of Applied Physiology 72, no. 2 (February 1, 1992): 447–54. http://dx.doi.org/10.1152/jappl.1992.72.2.447.
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To assess the effect of diaphragmatic ischemia on the inspiratory motor drive, we studied the in situ isolated and innervated left diaphragm in anesthetized, vagotomized, and mechanically ventilated dogs. The arterial and venous vessels of the left diaphragm were catheterized and isolated from the systemic circulation. Inspiratory muscle activation was assessed by recording the integrated electromyographic (EMG) activity of the left and right costal diaphragms and parasternal intercostal and alae nasi muscles. Tension generated by the left diaphragm during spontaneous breathing attempts was also measured. In eight animals, left diaphragmatic ischemia was induced by occluding the phrenic artery for 20 min, followed by 10 min of reperfusion. This elicited a progressive increase in EMG activity of the left and right diaphragms and parasternal and alae nasi muscles to 170, 157, 152, and 128% of baseline values, respectively, an increase in the frequency of breathing efforts, and no change in left diaphragmatic spontaneous tension. Thus the ratio of left diaphragmatic EMG to tension rose progressively during ischemia. During reperfusion, only the frequency of breathing efforts and alae nasi EMG recovered completely. In four additional animals, left diaphragmatic ischemia was induced after the left phrenic nerve was sectioned. Neither EMG activity of inspiratory muscles nor respiratory timing changed significantly during ischemia. In conclusion, diaphragmatic ischemia increases inspiratory motor drive through activation of phrenic afferents. The changes in alae nasi activity and respiratory timing indicate that this influence is achieved through supraspinal pathways.
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Matecki, Stefan, Roy W. R. Dudley, Maziar Divangahi, Renald Gilbert, Josephine Nalbantoglu, George Karpati, and Basil J. Petrof. "Therapeutic gene transfer to dystrophic diaphragm by an adenoviral vector deleted of all viral genes." American Journal of Physiology-Lung Cellular and Molecular Physiology 287, no. 3 (September 2004): L569—L576. http://dx.doi.org/10.1152/ajplung.00117.2004.
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Duchenne muscular dystrophy is caused by defects in the dystrophin gene, and the mdx mouse is the most frequently employed genetic model of this disease. It is well known that different muscle groups do not respond in the same way to dystrophin deficiency. In particular, the mdx mouse diaphragm exhibits severe morphological and functional changes not found in other mdx muscles. Use of early generation adenoviral vectors to deliver genes to the diaphragm in immunocompetent mdx mice has been associated with substantial functional toxicity and a rapid loss of transgene expression. Here we determined the response to dystrophin gene replacement in the mdx diaphragm using a “gutted” adenoviral vector that contains the coding sequence of two full-length dystrophin genes and is deleted of most viral DNA sequences. At 1 wk postdelivery of the vector, 23.6 ± 4% of total fibers in the injected diaphragm bundle expressed dystrophin at the sarcolemma, which remained stable over the study duration of 30 days without the need for continuous immunosuppression. Treated diaphragms showed a significantly improved resistance to the abnormal force deficits induced by high-stress muscle contractions, the latter being a functional hallmark of dystrophin-deficient muscle. This functional amelioration was achieved despite the presence of mildly increased inflammation (CD4+ and CD8+ lymphocytes) within the vector-treated diaphragms. To our knowledge, this is the first demonstration that a viral vector can achieve reversal of functional abnormalities in the dystrophic diaphragm via therapeutic dystrophin gene transfer without the need for sustained immunosuppressive therapy.
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Ammar, Tarek, Wei Lin, Amanda Higgins, Lawrence J. Hayward, and Jean-Marc Renaud. "Understanding the physiology of the asymptomatic diaphragm of the M1592V hyperkalemic periodic paralysis mouse." Journal of General Physiology 146, no. 6 (November 30, 2015): 509–25. http://dx.doi.org/10.1085/jgp.201511476.
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The diaphragm muscle of hyperkalemic periodic paralysis (HyperKPP) patients and of the M1592V HyperKPP mouse model rarely suffers from the myotonic and paralytic symptoms that occur in limb muscles. Enigmatically, HyperKPP diaphragm expresses the mutant NaV1.4 channel and, more importantly, has an abnormally high Na+ influx similar to that in extensor digitorum longus (EDL) and soleus, two hindlimb muscles suffering from the robust HyperKPP abnormalities. The objective was to uncover the physiological mechanisms that render HyperKPP diaphragm asymptomatic. A first mechanism involves efficient maintenance of resting membrane polarization in HyperKPP diaphragm at various extracellular K+ concentrations compared with larger membrane depolarizations in HyperKPP EDL and soleus. The improved resting membrane potential (EM) results from significantly increased Na+ K+ pump electrogenic activity, and not from an increased protein content. Action potential amplitude was greater in HyperKPP diaphragm than in HyperKPP soleus and EDL, providing a second mechanism for the asymptomatic behavior of the HyperKPP diaphragm. One suggested mechanism for the greater action potential amplitude is lower intracellular Na+ concentration because of greater Na+ K+ pump activity, allowing better Na+ current during the action potential depolarization phase. Finally, HyperKPP diaphragm had a greater capacity to generate force at depolarized EM compared with wild-type diaphragm. Action potential amplitude was not different between wild-type and HyperKPP diaphragm. There was also no evidence for an increased activity of the Na+–Ca2+ exchanger working in the reverse mode in the HyperKPP diaphragm compared with the wild-type diaphragm. So, a third mechanism remains to be elucidated to fully understand how HyperKPP diaphragm generates more force compared with wild type. Although the mechanism for the greater force at depolarized resting EM remains to be determined, this study provides support for the modulation of the Na+ K+ pump as a component of therapy to alleviate weakness in HyperKPP.
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Ameredes, Bill T., Jon F. Watchko, Monica J. Daood, J. Fernando Rosas, Michael P. Donahoe, and Robert M. Rogers. "Growth hormone restores aged diaphragm myosin composition and performance after chronic undernutrition." Journal of Applied Physiology 87, no. 4 (October 1, 1999): 1253–59. http://dx.doi.org/10.1152/jappl.1999.87.4.1253.
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The effects of growth hormone (GH) on diaphragm muscle myosin heavy chain (MHC) composition and mechanical performance were investigated in Fischer 344 male rats aged to senescence (24.5 mo of age). Chronic undernutrition (UN), refeeding (RF), and RF+GH were compared with ad libitum feeding by using a model of UN that produced a 50% decrease in body weight over a 12-mo period. The effect of aging was assessed by comparing MHC composition of ad libitum-fed rats at 12 and 24.5 mo of age. At senescence, significant decreases in slow type I (−23%) and fast type IIA (−31%) MHC had occurred with aging. Conversely, UN over this aging period increased types I (32–73%) and IIA (22–23%) MHC and decreased fast types IIB (32–54%) and IIX (30–31%) MHC. RF and RF+GH reversed these shifts back toward control values. At senescence, maximal specific force, maximal velocity, and specific power capacity were not different across treatment groups. During repetitive isotonic contraction trials, the diaphragms of UN rats maintained power production over time (54% of initial power at 60 s), whereas the power production of diaphragms of ad libitum-fed rats fell to 0% ( P < 0.05). In comparison with UN rats, the diaphragms of RF and RF+GH rats produced 23 (not significant) and 11% ( P < 0.05) of initial power, respectively, suggesting that RF+GH treatment restored performance characteristics after UN. We conclude that RF+GH can reverse alterations in MHC composition and mechanical performance produced by chronic UN in the aged rat diaphragm.
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Bazzy, A. R., and Y. J. Kim. "Effect of chronic respiratory load on cytochrome oxidase activity in diaphragmatic fibers." Journal of Applied Physiology 72, no. 1 (January 1, 1992): 266–71. http://dx.doi.org/10.1152/jappl.1992.72.1.266.
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To determine whether the increase in oxidative capacity after respiratory muscle training with chronic inspiratory loads in sheep is specific to a particular fiber type, we measured cytochrome c oxidase (COX) activity in type I and type II fibers. COX activity in individual fibers was examined histochemically and measured as relative optical density by use of an image processing system. Fiber types were differentiated by the myosin adenosine-triphosphatase reaction. We found that COX activity was higher in both fiber types in the trained diaphragms than in the control diaphragms (P less than 0.01). The increase with training was greater in type II (39%) than in type I fibers (21%), resulting in relatively homogeneous COX activity in all diaphragmatic fibers. The proportion of type I fibers increased from 43.4 +/- 5.4% in the control diaphragm to 53.1 +/- 2.9% in the trained diaphragm, whereas the proportion of type II fibers decreased (P less than 0.001). We conclude that respiratory muscle training activates oxidative enzyme activity in both diaphragmatic fiber types; this activation is differentially more in type II fibers, which also decrease in proportion, and less in type I fibers, which increase in proportion.
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Van Gammeren, Darin, Darin J. Falk, Melissa A. Deering, Keith C. DeRuisseau, and Scott K. Powers. "Diaphragmatic nitric oxide synthase is not induced during mechanical ventilation." Journal of Applied Physiology 102, no. 1 (January 2007): 157–62. http://dx.doi.org/10.1152/japplphysiol.00043.2006.
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Mechanical ventilation (MV) is associated with diaphragmatic oxidative stress that contributes to both diaphragmatic atrophy and contractile dysfunction. However, the pathways responsible for oxidant production in the diaphragm during MV remain unknown. To address this issue, we tested the hypothesis that diaphragmatic nitric oxide synthase (NOS) activity is elevated during MV, resulting in nitration of diaphragmatic proteins. Rats were mechanically ventilated for 18 h, and time-matched, anesthetized but spontaneously breathing animals served as controls. Protein levels of endothelial NOS, inducible NOS, and neuronal NOS were measured in diaphragms from all animals. 3-Nitrotyrosine levels were also measured as an index of protein nitration, and S-nitrosothiol levels were measured as a marker of nitric oxide reactions with molecules containing sulfhydryl groups. Levels of nitrates and nitrites were measured as markers of stable end products of nitric oxide metabolism. Finally, as a marker of oxidative stress, diaphragmatic levels of reduced GSH were also analyzed. MV did not promote an increase in diaphragmatic protein levels of endothelial NOS or neuronal NOS. Moreover, inducible NOS was not detected in the diaphragms of either experimental group. Consistent with these findings, MV did not elevate diaphragmatic 3-nitrotyrosine levels in any subcellular fraction of the diaphragm, including the cytosolic, mitochondrial, membrane, and insoluble protein fractions. Moreover, prolonged MV did not elevate diaphragmatic levels of S-nitrosothiols, nitrate, or nitrite. Finally, prolonged MV significantly reduced diaphragmatic levels of GSH, which is consistent with diaphragmatic oxidative stress. Collectively, these data reveal that MV-induced oxidative stress in the diaphragm is not due to increases in nitric oxide production by NOS.
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Pardo, Patricia S., Michael A. Lopez, and Aladin M. Boriek. "FOXO transcription factors are mechanosensitive and their regulation is altered with aging in the respiratory pump." American Journal of Physiology-Cell Physiology 294, no. 4 (April 2008): C1056—C1066. http://dx.doi.org/10.1152/ajpcell.00270.2007.
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The mechanical regulation of the forkhead box O (FOXO) subclass of transcription factors in the respiratory pump and its implication in aging are completely unknown. We investigated the effects of diaphragm stretch on three FOXO isoforms, Foxo1, Foxo3a, and Foxo4, in normal mice at different ages. We tested the hypotheses that 1) FOXO activities are regulated in response to diaphragm stretch and 2) mechanical properties of aging diaphragm are altered, leading to altered regulation of FOXO with aging. Our results showed that stretch downregulated FOXO DNA-binding activity by a mechanism that required Akt and IKK activation in young mice but that these pathways lost their mechanosensitivity with age. This aberrant regulation of FOXO with aging was associated with altered viscoelasticity, compliance, and extensibility of the aged diaphragm. Curiously, the dramatic decrease of the nuclear content of Foxo1 and Foxo3a, the two isoforms associated with muscle atrophy, with aging correlated with higher basal activation of Akt and IKK signaling in diaphragms of old mice. In contrast, the stability of Foxo4 in the nucleus became dependent on JNK, which is strongly activated in aged diaphragm. This finding suggests that Foxo4 was responsible for the FOXO-dependent transcriptional activity in aging diaphragm. Our data support the hypothesis that aging alters the mechanical properties of the respiratory pump, leading to altered mechanical regulation of the stretch-induced signaling pathways controlling FOXO activities. Our study supports a mechanosensitive signaling mechanism that is responsible for regulation of the FOXO transcription factors by aging.
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Evman, Serdar, and Mahmut Talha Dogruyol. "EMBRYOLOGY, ANATOMY AND PHYSIOLOGY OF THE DIAPHRAGM." Toraks Cerrahisi Bulteni 4, no. 4 (January 4, 2014): 225–29. http://dx.doi.org/10.5152/tcb.2013.35.
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Nair, Jayakrishnan, Kristi A. Streeter, Sara M. F. Turner, Michael D. Sunshine, Donald C. Bolser, Emily J. Fox, Paul W. Davenport, and David D. Fuller. "Anatomy and physiology of phrenic afferent neurons." Journal of Neurophysiology 118, no. 6 (December 1, 2017): 2975–90. http://dx.doi.org/10.1152/jn.00484.2017.
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Large-diameter myelinated phrenic afferents discharge in phase with diaphragm contraction, and smaller diameter fibers discharge across the respiratory cycle. In this article, we review the phrenic afferent literature and highlight areas in need of further study. We conclude that 1) activation of both myelinated and nonmyelinated phrenic sensory afferents can influence respiratory motor output on a breath-by-breath basis; 2) the relative impact of phrenic afferents substantially increases with diaphragm work and fatigue; 3) activation of phrenic afferents has a powerful impact on sympathetic motor outflow, and 4) phrenic afferents contribute to diaphragm somatosensation and the conscious perception of breathing. Much remains to be learned regarding the spinal and supraspinal distribution and synaptic contacts of myelinated and nonmyelinated phrenic afferents. Similarly, very little is known regarding the potential role of phrenic afferent neurons in triggering or modulating expression of respiratory neuroplasticity.
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Nguyen, Taitan, Joseph Shrager, Larry Kaiser, Lijuan Mei, Monica Daood, Jon Watchko, Neal Rubinstein, and Sanford Levine. "Developmental myosin heavy chains in the adult human diaphragm: coexpression patterns and effect of COPD." Journal of Applied Physiology 88, no. 4 (April 1, 2000): 1446–56. http://dx.doi.org/10.1152/jappl.2000.88.4.1446.
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In preliminary experiments we noted developmental (i.e., embryonic and neonatal) myosin heavy chains (MHCs) in the diaphragms of patients with severe chronic obstructive pulmonary disease (COPD). We hypothesized that this finding represented new fiber formation secondary to injury associated with the mechanical stress of COPD or previously undescribed MHCs in the human diaphragm. To distinguish between these possibilities, we analyzed diaphragmatic biopsies obtained from 9 patients with severe COPD (forced expiratory volume in 1 s = 21 ± 2% predicted, residual volume = 283 ± 22% predicted) and 10 age-matched controls. First, using immunocytochemistry with specific monoclonal antibodies, we noted that control diaphragms had greater proportions of fibers expressing embryonic (50 ± 2 vs. 28 ± 3%, P < 0.0001) and neonatal (52 ± 2 vs. 32 ± 3%, P < 0.001) MHCs than COPD diaphragms. Second, SDS-PAGE demonstrated that these developmental MHCs represented only a very small fraction of the diaphragmatic MHC content. Third, the RT-PCR demonstrated mRNA coding for embryonic and neonatal MHCs in COPD and control diaphragms. Last, COPD and control diaphragms exhibited normal histology on light microscopy. We conclude that the presence of developmental MHC isoforms does not indicate new fiber formation in diaphragms of patients with severe COPD. Although these results represent the first systematic description of embryonic and neonatal MHCs in normal adult human diaphragms, their function remains to be elucidated.
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Teitelbaum, J., C. O. Borel, S. Magder, R. J. Traystman, and S. N. Hussain. "Effect of selective diaphragmatic paralysis on the inspiratory motor drive." Journal of Applied Physiology 74, no. 5 (May 1, 1993): 2261–68. http://dx.doi.org/10.1152/jappl.1993.74.5.2261.
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Using alpha-chloralose-anesthetized mechanically ventilated vagotomized dogs, we assessed the effects of selective diaphragmatic paralysis on the inspiratory motor drive. Diaphragmatic paralysis was accomplished by a bolus injection of vecuronium, a neuromuscular junction blocker, into the left phrenic artery of an in situ vascularly isolated and innervated left diaphragm. The inspiratory motor drive during spontaneous breathing attempts was assessed by measuring peak integrated electromyographic (EMG) activities of the left and right diaphragms and parasternal and alae nasi muscles. Respiratory timing parameters were measured from the integrated EMG signals of the diaphragm. Three groups of dogs were studied. In group 1 (n = 9), vecuronium was injected into the phrenic artery with the left diaphragmatic length adjusted at the functional residual capacity. Vecuronium injection (0.2 mg) resulted in a significant decline in left diaphragmatic tension and integrated EMG. Breathing frequency increased by 24% of the baseline value, whereas right diaphragm, parasternal, and alae nasi EMG activities rose to 136, 227, and 165% of their respective baseline values a few seconds after the vecuronium injection. In group 2 (n = 6), vecuronium injection in left phrenectomized animals did not alter the EMG activities of the inspiratory muscles (left EMG signal was abolished) nor did it alter respiratory timing. In group 3 (n = 4), the left diaphragm was placed in a flaccid position. Vecuronium injection in this group did not produce any changes in the EMG activities or respiratory timing. We conclude that selective diaphragmatic paralysis elicits a significant rise in the inspiratory motor drive. This effect is likely to be mediated through the inhibition of diaphragmatic Golgi tendon organ activity.
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Lopez, Michael A., Patricia S. Pardo, Gregory A. Cox, and Aladin M. Boriek. "Early mechanical dysfunction of the diaphragm in the muscular dystrophy with myositis (Ttnmdm) model." American Journal of Physiology-Cell Physiology 295, no. 5 (November 2008): C1092—C1102. http://dx.doi.org/10.1152/ajpcell.16.2008.
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A complex rearrangement mutation in the mouse titin gene leads to an in-frame 83-amino acid deletion in the N2A region of titin. Autosomal recessive inheritance of the titin muscular dystrophy with myositis ( Ttn mdm/mdm) mutation leads to a severe early-onset muscular dystrophy and premature death. We hypothesized that the N2A deletion would negatively impact the force-generating capacity and passive mechanical properties of the mdm diaphragm. We measured in vitro active isometric contractile and passive length-tension properties to assess muscle function at 2 and 6 wk of age. Micro-CT, myosin heavy chain Western blotting, and histology were used to assess diaphragm structure. Marked chest wall distortions began at 2 wk and progressively worsened until 5 wk. The percentage of myofibers with centrally located nuclei in mdm mice was significantly ( P < 0.01) increased at 2 and 6 wk by 4% and 17%, respectively, compared with controls. At 6 wk, mdm diaphragm twitch stress was significantly ( P < 0.01) reduced by 71%, time to peak twitch was significantly ( P < 0.05) reduced by 52%, and half-relaxation time was significantly ( P < 0.05) reduced by 57%. Isometric tetanic stress was significantly ( P < 0.05) depressed in 2- and 6-wk mdm diaphragms by as much as 64%. Length-tension relationships of the 2- and 6-wk mdm diaphragms showed significantly ( P < 0.05) decreased extensibility and increased stiffness. Slow myosin heavy chain expression was aberrantly favored in the mdm diaphragm at 6 wk. Our data strongly support early contractile and passive mechanical aberrations of the respiratory pump in mdm mice.
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Beck, Jennifer, Christer Sinderby, Lars Lindström, and Alex Grassino. "Effects of lung volume on diaphragm EMG signal strength during voluntary contractions." Journal of Applied Physiology 85, no. 3 (September 1, 1998): 1123–34. http://dx.doi.org/10.1152/jappl.1998.85.3.1123.
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The use of esophageal recordings of the diaphragm electromyogram (EMG) signal strength to evaluate diaphragm activation during voluntary contractions in humans has recently been criticized because of a possible artifact created by changes in lung volume. Therefore, the first aim of this study was to evaluate whether there is an artifactual influence of lung volume on the strength of the diaphragm EMG during voluntary contractions. The second aim was to measure the required changes in activation for changes in lung volume at a given tension, i.e., the volume-activation relationship of the diaphragm. Healthy subjects ( n = 6) performed contractions of the diaphragm at different transdiaphragmatic pressure (Pdi) targets (range 20–160 cmH2O) while maintaining chest wall configuration constant at different lung volumes. The diaphragm EMG was recorded with a multiple-array esophageal electrode, with control of signal contamination and electrode positioning. The effects of lung volume on the EMG were studied by comparing the crural diaphragm EMG root mean square (RMS), an index of crural diaphragm activation, with an index of global diaphragm activation obtained by normalizing Pdi to the maximum Pdi at the given muscle length (Pdi/P[Formula: see text]) at the different lung volumes. We observed a direct relationship between RMS and Pdi/P[Formula: see text]independent of diaphragm length. The volume-activation relationship of the diaphragm was equally affected by changes in lung volume as the volume-Pdi relationship (60% change from functional residual capacity to total lung capacity). We conclude that the RMS of the diaphragm EMG is not artifactually influenced by lung volume and can be used as a reliable index of diaphragm activation. The volume-activation relationship can be used to infer changes in the length-tension relationship of the diaphragm at submaximal activation/contraction levels.
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Lopez, M. A., U. Mayer, W. Hwang, T. Taylor, M. A. Hashmi, S. R. Jannapureddy, and Aladin M. Boriek. "Force transmission, compliance, and viscoelasticity are altered in the α7-integrin-null mouse diaphragm." American Journal of Physiology-Cell Physiology 288, no. 2 (February 2005): C282—C289. http://dx.doi.org/10.1152/ajpcell.00362.2003.
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α7β1 integrin is a transmembrane structural and receptor protein of skeletal muscles, and the absence of α7-integrin causes muscular dystrophy. We hypothesized that the absence of α7-integrin alters compliance and viscoelasticity and disrupts the mechanical coupling between passive transverse and axial contractile elements in the diaphragm. In vivo the diaphragm is loaded with pressure, and therefore axial and transverse length-tension relationships are important in assessing its function. We determined diaphragm passive length-tension relationships and the viscoelastic properties of its muscle in 1-month-old α7-integrin-null mice and age-matched controls. Furthermore, we measured the isometric contractile properties of the diaphragm from mutant and normal mice in the absence and presence of passive force applied in the transverse direction to fibers in 1-month-old and 5-month-old mutant mice. We found that compared with controls, the diaphragm direction of α7-integrin-null mutants showed 1) a significant decrease in muscle extensibility in 1-year-old mice, whereas muscle extensibility increased in the 1-month-old mice; 2) altered muscle viscoelasticity in the transverse direction of the muscle fibers of 1-month-old mice; 3) a significant increase in force-generating capacity in the diaphragms of 1-month-old mice, whereas in 5-month-old mice muscle contractility was depressed; and 4) significant reductions in mechanical coupling between longitudinal and transverse properties of the muscle fibers of 1-month-old mice. These findings suggest that α7-integrin serves an important mechanical function in the diaphragm by contributing to passive compliance, viscoelasticity, and modulation of its muscle contractile properties.
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Greybeck, Brad J., Matthew Wettergreen, Rolf D. Hubmayr, and Aladin M. Boriek. "Diaphragm curvature modulates the relationship between muscle shortening and volume displacement." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 301, no. 1 (July 2011): R76—R82. http://dx.doi.org/10.1152/ajpregu.00673.2010.
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During physiological spontaneous breathing maneuvers, the diaphragm displaces volume while maintaining curvature. However, with maximal diaphragm activation, curvature decreases sharply. We tested the hypotheses that the relationship between diaphragm muscle shortening and volume displacement (VD) is nonlinear and that curvature is a determinant of such a relationship. Radiopaque markers were surgically placed on three neighboring muscle fibers in the midcostal region of the diaphragm in six dogs. The three-dimensional locations were determined using biplanar fluoroscopy and diaphragm VD, curvature, and muscle shortening were computed in the prone and supine postures during spontaneous breathing (SB), spontaneous inspiration efforts after airway occlusion at lung volumes ranging from functional residual capacity (FRC) to total lung capacity, and during bilateral maximal phrenic nerve stimulation at those same lung volumes. In supine dogs, diaphragm VD was approximately two- to three-fold greater during maximal phrenic nerve stimulation than during SB. The contribution of muscle shortening to VD nonlinearly increases with level of diaphragm activation independent of posture. During submaximal diaphragm activation, the contribution is essentially linear due to constancy of diaphragm curvature in both the prone and supine posture. However, the sudden loss of curvature during maximal bilateral phrenic nerve stimulation at muscle shortening values greater than 40% (ΔL/LFRC) causes a nonlinear increase in the contribution of muscle shortening to diaphragm VD, which is concomitant with a nonlinear change in diaphragm curvature. We conclude that the nonlinear relationship between diaphragm muscle shortening and its VD is, in part, due to a loss of its curvature at extreme muscle shortening.
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Nethery, D., D. Stofan, L. Callahan, A. DiMarco, and G. Supinski. "Formation of reactive oxygen species by the contracting diaphragm is PLA2dependent." Journal of Applied Physiology 87, no. 2 (August 1, 1999): 792–800. http://dx.doi.org/10.1152/jappl.1999.87.2.792.
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Recent work indicates that respiratory muscles generate superoxide radicals during contraction (M. B. Reid, K. E. Haack, K. M. Francik, P. A. Volberg, L. Kabzik, and M. S. West. J. Appl. Physiol. 73: 1797–1804, 1992). The intracellular pathways involved in this process are, however, unknown. The purpose of the present study was to test the hypothesis that contraction-related formation of reactive oxygen species (ROS) by skeletal muscle is linked to activation of the 14-kDa isoform of phospholipase A2(PLA2). Studies were performed by using an in vitro hemidiaphragm preparation submerged in an organ bath, and formation of ROS in muscles was assessed by using a recently described fluorescent indicator technique. We examined ROS formation in resting and contracting muscle preparations and then determined whether contraction-related ROS generation could be altered by administration of various PLA2 inhibitors: manoalide and aristolochic acid, both inhibitors of 14-kDa PLA2; arachidonyltrifluoromethyl ketone (AACOCF3), an inhibitor of 85-kDa PLA2; and haloenol lactone suicide substrate (HELSS), an inhibitor of calcium-independent PLA2. We found 1) little ROS formation [2.0 ± 0.8 (SE) ng/mg] in noncontracting control diaphragms, 2) a high level of ROS (20.0 ± 2.0 ng/mg) in electrically stimulated contracting diaphragms (trains of 20-Hz stimuli for 10 min, train rate 0.25 s−1), 3) near-complete suppression of ROS generation in manoalide (3.0 ± 0.5 ng/mg, P < 0.001)- and aristolochic acid-treated contracting diaphragms (4.0 ± 1.0 ng/mg, P < 0.001), and 4) no effect of AACOCF3 or HELSS on ROS formation in contracting diaphragm. During in vitro studies examining fluorescent measurement of ROS formation in response to a hypoxanthine/xanthine oxidase superoxide-generating solution, manoalide, aristolochic acid, AACOCF3, and HELSS had no effect on signal intensity. These data indicate that ROS formation by contracting diaphragm muscle can be suppressed by the administration of inhibitors of the 14-kDa isoform of PLA2 and suggest that this enzyme plays a critical role in modulating ROS formation during muscle contraction.
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Nguyen, D. A. T., N. Amirjani, E. J. McCaughey, S. C. Gandevia, J. E. Butler, and A. L. Hudson. "Differential activation of the human costal and crural diaphragm during voluntary and involuntary breaths." Journal of Applied Physiology 128, no. 5 (May 1, 2020): 1262–70. http://dx.doi.org/10.1152/japplphysiol.00790.2019.
Full textAbstract:
Simultaneous electromyographic recordings from the human costal and crural diaphragm during voluntary augmented breathing and involuntary rebreathing show that the increase in inspiratory crural diaphragm activity was ~60% of the increase in costal diaphragm activity. However costal to crural diaphragm activation did not differ between the two tasks. The dissociation in the amplitude of activation of the costal and crural diaphragm becomes apparent only as the drive to breathe increases above tidal breathing.
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Greising, Sarah M., Coen A. C. Ottenheijm, Ken D. O’Halloran, and Esther Barreiro. "Diaphragm plasticity in aging and disease: therapies for muscle weakness go from strength to strength." Journal of Applied Physiology 125, no. 2 (August 1, 2018): 243–53. http://dx.doi.org/10.1152/japplphysiol.01059.2017.
Full textAbstract:
The diaphragm is the main inspiratory muscle and is required to be highly active throughout the life span. The diaphragm muscle must be able to produce and sustain various behaviors that range from ventilatory to nonventilatory such as those required for airway maintenance and clearance. Throughout the life span various circumstances and conditions may affect the ability of the diaphragm muscle to generate requisite forces, and in turn the diaphragm muscle may undergo significant weakness and dysfunction. For example, hypoxic stress, critical illness, cancer cachexia, chronic obstructive pulmonary disorder, and age-related sarcopenia all represent conditions in which significant diaphragm muscle dysfunction exits. This perspective review article presents several interesting topics involving diaphragm plasticity in aging and disease that were presented at the International Union of Physiological Sciences Conference in 2017. This review seeks to maximize the broad and collective research impact on diaphragm muscle dysfunction in the search for transformative treatment approaches to improve the diaphragm muscle health during aging and disease.
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Wilson, Theodore A., and Andre De Troyer. "Diagrammatic analysis of the respiratory action of the diaphragm." Journal of Applied Physiology 108, no. 2 (February 2010): 251–55. http://dx.doi.org/10.1152/japplphysiol.00960.2009.
Full textAbstract:
During isolated phrenic nerve stimulation, the muscles of the diaphragm shorten by 40–50% of their optimal length, and the force in the muscle and transdiaphragmatic pressure (Pdi) depend on the final muscle length. The muscle shortening depends on the load imposed on the diaphragm by pleural and abdominal pressures during a particular maneuver. The mechanics of the interaction between the diaphragm and the load is well understood, but the force-length properties of the diaphragm are nonlinear, and an algebraic analysis of the interaction is clumsy. Here we describe a graphical analysis of the interaction. The variable muscle length is transformed into an equivalent variable, i.e., volume displaced by the diaphragm (Vdi), to obtain the characteristic line for the diaphragm, a graph of Pdi vs. Vdi for a given level of activation. The load is described by the same variables. Therefore, load lines can be drawn on the same graph, and the equilibrium point for the diaphragm is given by the intersection of the load line with the characteristic line of the diaphragm. Graphical analyses of the volume dependence of the respiratory effects of diaphragm and intercostal muscle activation and for the interaction between them are shown.
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Drumond, M. C., and W. M. Deen. "Hindered Transport of Macromolecules Through a Single Row of Cylinders: Application to Glomerular Filtration." Journal of Biomechanical Engineering 117, no. 4 (November 1, 1995): 414–22. http://dx.doi.org/10.1115/1.2794202.
Full textAbstract:
The slit diaphragms of renal glomerular capillaries form an ultrafiltration barrier which may be approximated as a row of cylindrical fibers of macromolecular dimensions. To describe the hindered transport of plasma proteins and other macromolecules through this barrier, we developed an approximate hydrodynamic model for spherical, Brownian particles passing through a row of infinitely long cylinders. The selectivity of the slit diaphragm was assessed by computing concentration profiles for a wide range of molecular sizes for Pe ≤ 1, where Pe is a Peclet number based on the cylinder radius. The sieving coefficient for the slit diaphragm was computed as θSD = CB/CO, where CO was the average concentration at a specified distance upstream from the cylinders (corresponding to the location of the basement membrane), and CB was the concentration far downstream (corresponding to Bowman’s space). The results of previous experimental sieving studies using rats could be accounted for approximately by postulating a wide distribution of spacings between the fibers of the slit diaphragm. Comparing the results for θSD with calculations for a model of the glomerular basement membrane suggests that the slit diaphragm is by far the more size-restrictive part of the overall barrier.
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Heunks, Leo M. A., Aalt Bast, Cees L. A. van Herwaarden, Guido R. M. M. Haenen, and P. N. Richard Dekhuijzen. "Effects of emphysema and training on glutathione oxidation in the hamster diaphragm." Journal of Applied Physiology 88, no. 6 (June 1, 2000): 2054–61. http://dx.doi.org/10.1152/jappl.2000.88.6.2054.
Full textAbstract:
Loading of skeletal muscles is associated with increased generation of oxidants, which in turn may impair muscle contractility. We investigated whether the load on the hamster diaphragm imposed by pulmonary emphysema induces oxidative stress, as indicated by glutathione oxidation, and whether the degree of glutathione oxidation is correlated with contractility of the diaphragm. In addition, the effect of 12 wk of treadmill exercise training on contractility and glutathione content in the normal (NH) and emphysematous hamster (EH) diaphragm was investigated. Training started 6 mo after elastase instillation. After the training period, glutathione content and in vitro contractility of the diaphragm were determined. Twitch force and maximal tetanic force were significantly reduced (by ∼30 and ∼15%, respectively) in EH compared with NH. In sedentary hamsters, the GSSG-to-GSH ratio was significantly elevated in the EH compared with the NH diaphragm. A significant inverse correlation was found between GSSG-to-GSH ratio and twitch force in the diaphragm ( P < 0.01). Training improved maximal tetanic force and reduced fatigability of the EH diaphragm but did not alter its glutathione content. In conclusion, 1) emphysema induces oxidative stress in the diaphragm, 2) training improves the contractile properties of the EH diaphragm, and 3) this improvement is not accompanied by changes in glutathione redox status.
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Kawachi, Hiroshi, Hidetake Kurihara, Peter S. Topham, Dennis Brown, Michael A. Shia, Michiaki Orikasa, Fujio Shimizu, and David J. Salant. "Slit diaphragm-reactive nephritogenic MAb 5-1-6 alters expression of ZO-1 in rat podocytes." American Journal of Physiology-Renal Physiology 273, no. 6 (December 1, 1997): F984—F993. http://dx.doi.org/10.1152/ajprenal.1997.273.6.f984.
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Monoclonal antibody (MAb) 5-1-6 identifies a 51-kDa protein (p51) on rat podocyte foot processes and causes severe complement- and leukocyte-independent proteinuria when injected into rats. In the studies reported here, we used various immunohistological techniques to define the precise location of p51 and its relationship to ZO-1, a known component of the podocyte slit diaphragm in adult rat glomeruli. Our results demonstrate that p51 and ZO-1 lie close to each other on opposite sides of the podocyte plasma membrane at the point of insertion of the slit diaphragm: ZO-1 on the cytoplasmic face and p51 on the slit diaphragm and adjoining outer leaflet of the plasma membrane bordering the filtration slits. In addition to their geographic proximity, there appears to be a relationship between p51 and ZO-1. After MAb 5-1-6 injection, there was a progressive decline in stainable ZO-1 in the podocytes of heavily proteinuric rats. In addition, Western blot analysis of glomerular lysates showed that the decline in staining was due to a loss of immunoreactive ZO-1 rather than redistribution or diffusion of the protein. Simultaneously, the distribution of glomerular-bound MAb 5-1-6 became more clumped, apparently because of partial endocytosis into a lysosomal compartment, while the slit diaphragms remained morphologically intact. These findings suggest that MAb 5-1-6 alters the molecular composition of the slit diaphragm and thereby affects the glomerular permeability barrier.
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Kolbeck, R. C., and T. M. Nosek. "Fatigue of rapid and slow onset in isolated perfused rat and mouse diaphragms." Journal of Applied Physiology 77, no. 4 (October 1, 1994): 1991–98. http://dx.doi.org/10.1152/jappl.1994.77.4.1991.
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Muscle fatigue was studied in the isolated perfused rat (66% oxidative fibers) and mouse (99% oxidative fibers) diaphragms. Both muscles displayed two fatigue patterns when exposed to 333-ms trains of 20-Hz stimulation. A rapid fatigue pattern appeared within each contractile train as an immediate progressive twitch-by-twitch diminution in contractility [a decrease in maximal isometric twitch tension (T) and maximal rate of T development]. An intertrain slow fatigue pattern also appeared as a progressive train-by-train diminution in contractility and an increased maximal rate of relaxation normalized to T. A reduction in the stimulatory frequency from 20 to 2 Hz caused a considerable diminution in the rapid fatigue pattern. These data suggest that rapid fatigue results from the time course of mechanical restitution, the time necessary for the Ca2+ channels of the sarcoplasmic reticulum to recover from inactivation. The slow fatigue pattern, on the other hand, is thought to be due to changes in the intracellular milieu. The difference in sensitivity of the rat and mouse diaphragms to rapid and slow fatigue is apparently related to differences in their fiber type composition. Thus, as would be expected, the mouse diaphragm, composed of only oxidative fibers, is less susceptible to slow fatigue compared with the rat diaphragm. On the other hand, it is more susceptible to rapid fatigue.
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Cohn, David, Joshua O. Benditt, Scott Eveloff, and F. Dennis McCool. "Diaphragm thickening during inspiration." Journal of Applied Physiology 83, no. 1 (July 1, 1997): 291–96. http://dx.doi.org/10.1152/jappl.1997.83.1.291.
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Cohn, David, Joshua O. Benditt, Scott Eveloff, and F. Dennis McCool. Diaphragm thickening during inspiration. J. Appl. Physiol. 83(1): 291–296, 1997.—Ultrasound has been used to measure diaphragm thickness ( T di) in the area where the diaphragm abuts the rib cage (zone of apposition). However, the degree of diaphragm thickening during inspiration reported as obtained by one-dimensional M-mode ultrasound was greater than that predicted by using other radiographic techniques. Because two-dimensional (2-D) ultrasound provides greater anatomic definition of the diaphragm and neighboring structures, we used this technique to reevaluate the relationship between lung volume and T di. We first established the accuracy and reproducibility of 2-D ultrasound by measuring T diwith a 7.5-MHz transducer in 26 cadavers. We found that T di measured by ultrasound correlated significantly with that measured by ruler ( R 2 = 0.89), with the slope of this relationship approximating a line of identity ( y = 0.89 x + 0.04 mm). The relationship between lung volume and T di was then studied in nine subjects by obtaining diaphragm images at the five target lung volumes [25% increments from residual volume (RV) to total lung capacity (TLC)]. Plots of T di vs. lung volume demonstrated that the diaphragm thickened as lung volume increased, with a more rapid rate of thickening at the higher lung volumes [ T di = 1.74 vital capacity (VC)2 + 0.26 VC + 2.7 mm] ( R 2= 0.99; P < 0.001) where lung volume is expressed as a fraction of VC. The mean increase in T di between RV and TLC for the group was 54% (range 42–78%). We conclude that 2-D ultrasound can accurately measure T di and that the average thickening of the diaphragm when a subject is inhaling from RV to TLC using this technique is in the range of what would be predicted from a 35% shortening of the diaphragm.
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Supinski, G. S., A. F. DiMarco, J. Gonzalez, and M. D. Altose. "Effect of norepinephrine on diaphragm contractility and blood flow." Journal of Applied Physiology 69, no. 6 (December 1, 1990): 2019–28. http://dx.doi.org/10.1152/jappl.1990.69.6.2019.
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Recent studies have shown that diaphragm fatigue can be reversed by mechanical augmentation of phrenic arterial flow. The purpose of the present experiment was to determine whether it was possible to pharmacologically augment diaphragm blood flow and reverse fatigue by the administration of norepinephrine. Four groups of studies were performed, all employing our previously described in situ isometric canine diaphragm strip preparation (Supinski et al., J. Appl. Physiol. 60: 1789-1796, 1986). Group I studies examined the effects of norepinephrine on the contractility of the nonfatigued diaphragm in normotensive dogs, group II studies examined the effects of this drug on the contractility of the fatigued diaphragm in normotensive animals, and group III studies examined the effect of this drug on the contractility of the fatigued diaphragm in hypotensive animals. Group IV studies examined the effect of norepinephrine in normotensive animals in which the phrenic artery was cannulated and pump perfused at constant flow. Fatigue was induced in group II, III, and IV studies by rhythmically stimulating the diaphragm via intramuscular electrodes. Norepinephrine had no effect on the contractility of the nonfatigued diaphragm (group I). In normotensive (group II) and hypotensive animals (group III), norepinephrine elicited dramatic increases in arterial blood pressure and phrenic arterial flow and produced a significant upshift in the force-frequency curve of the fatigued diaphragm. However, when phrenic flow was held constant (group IV experiments), norepinephrine failed to augment the contractility of the fatigued diaphragm. These results indicate that 1) norepinephrine can increase phrenic blood flow and augment the contractility of the fatigued diaphragm in both normotensive and hypotensive conditions and 2) this effect of norepinephrine to partially reverse fatigue is secondary to its action to augment diaphragmatic blood flow.
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Beck, Jennifer, Christer Sinderby, Lars Lindström, and Alex Grassino. "Diaphragm interference pattern EMG and compound muscle action potentials: effects of chest wall configuration." Journal of Applied Physiology 82, no. 2 (February 1, 1997): 520–30. http://dx.doi.org/10.1152/jappl.1997.82.2.520.
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Beck, Jennifer, Christer Sinderby, Lars Lindström, and Alex Grassino. Diaphragm interference pattern EMG and compound muscle action potentials: effects of chest wall configuration. J. Appl. Physiol. 82(2): 520–530, 1997.—The effect of chest wall configuration on the diaphragm electromyogram (EMGdi) was evaluated in five healthy subjects with an esophageal electrode for both interference pattern EMGdi (voluntary contractions) and electrically evoked diaphragm compound muscle action potentials (CMAPs). Diaphragm CMAPs (both unilateral and bilateral) were evaluated for the baseline-to-peak amplitude (Ampl), the time from the onset of the CMAP to first peak (T1), root mean square (RMS), and center frequency (CF) values of the CMAP power spectrum. CF values from the interference pattern EMGdi power spectrum were also calculated. For CMAPs obtained at an electrode position least influenced by variations induced by electrode positioning, Ampl increased with diaphragm shortening from functional residual capacity (FRC) to total lung capacity (TLC) by 101 and 98% (unilateral and bilateral, respectively). Bilateral CMAP RMS values increased 116% from FRC to TLC. CMAP T1 values decreased with diaphragm shortening from FRC to TLC by 1.1 and 2.1 ms for the unilateral and bilateral stimulations, respectively, and CF increased for the bilateral diaphragm CMAPs with diaphragm shortening. CF values from the interference pattern EMGdi did not show any consistent change with chest wall configuration. Thus CF values of the interference pattern EMGdi obtained with an esophageal electrode can be considered reliable for physiological interpretation, at any diaphragm length (if electrode positioning and signal contamination are controlled for), contrary to the diaphragm CMAPs, which are sensitive to changes in chest wall configuration. It is speculated that the different results (over the effects of chest wall configuration on interference pattern EMGdi and diaphragm CMAPs) may be because of summation properties of the signals and how these influence the EMG power spectrum.
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Supinski, Gerald S., Lin Wang, Elizabeth A. Schroder, and Leigh Ann P. Callahan. "SS31, a mitochondrially targeted antioxidant, prevents sepsis-induced reductions in diaphragm strength and endurance." Journal of Applied Physiology 128, no. 3 (March 1, 2020): 463–72. http://dx.doi.org/10.1152/japplphysiol.00240.2019.
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Sepsis-induced diaphragm dysfunction contributes to respiratory failure and mortality in critical illness. There are no treatments for this form of diaphragm weakness. Studies show that sepsis-induced muscle dysfunction is triggered by enhanced mitochondrial free radical generation. We tested the hypothesis that SS31, a mitochondrially targeted antioxidant, would attenuate sepsis-induced diaphragm dysfunction. Four groups of mice were studied: 1) sham-operated controls, 2) sham-operated+SS31 (10 mg·kg−1·day−1), 3) cecal ligation puncture (CLP), and 4) CLP+SS31. Forty-eight hours postoperatively, diaphragm strips with attached phrenic nerves were isolated, and the following were assessed: muscle-field-stimulated force-frequency curves, nerve-stimulated force-frequency curves, and muscle fatigue. We also measured calpain activity, 20S proteasomal activity, myosin heavy chain (MHC) levels, mitochondrial function, and aconitase activity, an index of mitochondrial superoxide generation. Sepsis markedly reduced diaphragm force generation; SS31 prevented these decrements. Diaphragm-specific force generation averaged 30.2 ± 1.4, 9.4 ± 1.8, 25.5 ± 2.3, and 27.9 ± 0.6 N/cm2 for sham, CLP, sham+SS31, and CLP+SS31 groups ( P < 0.001). Similarly, with phrenic nerve stimulation, CLP depressed diaphragm force generation, effects prevented by SS31. During endurance trials, force was significantly reduced with CLP, and SS31 prevented these reductions ( P < 0.001). Sepsis also increased diaphragm calpain activity, increased 20S proteasomal activity, decreased MHC levels, reduced mitochondrial function (state 3 rates and ATP generation), and reduced aconitase activity; SS31 prevented each of these sepsis-induced alterations ( P ≤ 0.017 for all indices). SS31 prevents sepsis-induced diaphragm dysfunction, preserving force generation, endurance, and mitochondrial function. Compounds with similar mechanisms of action may be useful therapeutically to preserve diaphragm function in patients who are septic and critically ill. NEW & NOTEWORTHY Sepsis-induced diaphragm dysfunction is a major contributor to mortality and morbidity in patients with critical illness in intensive care units. Currently, there is no proven pharmacological treatment for this problem. This study provides the novel finding that administration of SS31, a mitochondrially targeted antioxidant, preserves diaphragm myosin heavy chain content and mitochondrial function, thereby preventing diaphragm weakness and fatigue in sepsis.