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Author: Grafiati
Published: 25 May 2024

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1

De Giorgio, Daria, Deborah Novelli, Francesca Motta, Marianna Cerrato, Davide Olivari, Annasimon Salama, Francesca Fumagalli, et al. "Characterization of the Cardiac Structure and Function of Conscious D2.B10-Dmdmdx/J (D2-mdx) mice from 16–17 to 24–25 Weeks of Age." International Journal of Molecular Sciences 24, no. 14 (July 22, 2023): 11805. http://dx.doi.org/10.3390/ijms241411805.

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Duchenne muscular dystrophy (DMD) is the most common form of muscle degenerative hereditary disease. Muscular replacement by fibrosis and calcification are the principal causes of progressive and severe musculoskeletal, respiratory, and cardiac dysfunction. To date, the D2.B10-Dmdmdx/J (D2-mdx) model is proposed as the closest to DMD, but the results are controversial. In this study, the cardiac structure and function was characterized in D2-mdx mice from 16–17 up to 24–25 weeks of age. Echocardiographic assessment in conscious mice, gross pathology, and histological and cardiac biomarker analyses were performed. At 16–17 weeks of age, D2-mdx mice presented mild left ventricular function impairment and increased pulmonary vascular resistance. Cardiac fibrosis was more extended in the right ventricle, principally on the epicardium. In 24–25-week-old D2-mdx mice, functional and structural alterations increased but with large individual variation. High-sensitivity cardiac Troponin T, but not N-terminal pro-atrial natriuretic peptide, plasma levels were increased. In conclusion, left ventricle remodeling was mild to moderate in both young and adult mice. We confirmed that right ventricle epicardial fibrosis is the most outstanding finding in D2-mdx mice. Further long-term studies are needed to evaluate whether this mouse model can also be considered a model of DMD cardiomyopathy.
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2

Hassani, Medhi, Dylan Moutachi, Mégane Lemaitre, Alexis Boulinguiez, Denis Furling, Onnik Agbulut, and Arnaud Ferry. "Beneficial effects of resistance training on both mild and severe mouse dystrophic muscle function as a preclinical option for Duchenne muscular dystrophy." PLOS ONE 19, no. 3 (March 8, 2024): e0295700. http://dx.doi.org/10.1371/journal.pone.0295700.

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Mechanical overloading (OVL) resulting from the ablation of muscle agonists, a supra-physiological model of resistance training, reduces skeletal muscle fragility, i.e. the immediate maximal force drop following lengthening contractions, and increases maximal force production, in mdx mice, a murine model of Duchene muscular dystrophy (DMD). Here, we further analyzed these beneficial effects of OVL by determining whether they were blocked by cyclosporin, an inhibitor of the calcineurin pathway, and whether there were also observed in the D2-mdx mice, a more severe murine DMD model. We found that cyclosporin did not block the beneficial effect of 1-month OVL on plantaris muscle fragility in mdx mice, nor did it limit the increases in maximal force and muscle weight (an index of hypertrophy). Fragility and maximal force were also ameliorated by OVL in the plantaris muscle of D2-mdx mice. In addition, OVL increased the expression of utrophin, cytoplamic γ-actin, MyoD, and p-Akt in the D2-mdx mice, proteins playing an important role in fragility, maximal force gain and muscle growth. In conclusion, OVL reduced fragility and increased maximal force in the more frequently used mild mdx model but also in D2-mdx mice, a severe model of DMD, closer to human physiopathology. Moreover, these beneficial effects of OVL did not seem to be related to the activation of the calcineurin pathway. Thus, this preclinical study suggests that resistance training could have a potential benefit in the improvement of the quality of life of DMD patients.
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3

Hayes, Holly M., Julie Angerosa, Adam T. Piers, Jason D. White, Jane Koleff, Madeline Thurgood, Jessica Moody, Michael M. Cheung, and Salvatore Pepe. "Preserved Left Ventricular Function despite Myocardial Fibrosis and Myopathy in the Dystrophin-Deficient D2.B10-Dmdmdx/J Mouse." Oxidative Medicine and Cellular Longevity 2022 (March 16, 2022): 1–19. http://dx.doi.org/10.1155/2022/5362115.

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Duchenne muscular dystrophy involves an absence of dystrophin, a cytoskeletal protein which supports cell structural integrity and scaffolding for signalling molecules in myocytes. Affected individuals experience progressive muscle degeneration that leads to irreversible loss of ambulation and respiratory diaphragm function. Although clinical management has greatly advanced, heart failure due to myocardial cell loss and fibrosis remains the major cause of death. We examined cardiac morphology and function in D2.B10-Dmdmdx/J (D2-mdx) mice, a relatively new mouse model of muscular dystrophy, which we compared to their wild-type background DBA/2J mice (DBA/2). We also tested whether drug treatment with a specific blocker of mitochondrial permeability transition pore opening (Debio-025), or ACE inhibition (Perindopril), had any effect on dystrophy-related cardiomyopathy. D2-mdx mice were treated for six weeks with Vehicle control, Debio-025 (20 mg/kg/day), Perindopril (2 mg/kg/day), or a combination ( n = 8 /group). At 18 weeks, compared to DBA/2, D2-mdx hearts displayed greater ventricular collagen, lower cell density, greater cell diameter, and greater protein expression levels of IL-6, TLR4, BAX/Bcl2, caspase-3, PGC-1α, and notably monoamine oxidases A and B. Remarkably, these adaptations in D2-mdx mice were associated with preserved resting left ventricular function similar to DBA/2 mice. Compared to vehicle, although Perindopril partly attenuated the increase in heart weight and collagen at 18 weeks, the drug treatments had no marked impact on dystrophic cardiomyopathy.
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4

Krishna, Swathy, Tiffany Quindry, Matthew B. Hudson, John C. Quindry, and Joshua T. Selsby. "Defective Autophagic Degradation in Aged D2‐mdx Diaphragms." FASEB Journal 34, S1 (April 2020): 1. http://dx.doi.org/10.1096/fasebj.2020.34.s1.04955.

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5

Yarlagadda, Sai, Christina Kulis, Peter G. Noakes, and Mark L. Smythe. "Hematopoietic Prostaglandin D Synthase Inhibitor PK007 Decreases Muscle Necrosis in DMD mdx Model Mice." Life 11, no. 9 (September 21, 2021): 994. http://dx.doi.org/10.3390/life11090994.

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Duchenne muscular dystrophy (DMD) is characterized by progressive muscle weakness and wasting due to the lack of dystrophin protein. The acute phase of DMD is characterized by muscle necrosis and increased levels of the pro-inflammatory mediator, prostaglandin D2 (PGD2). Inhibiting the production of PGD2 by inhibiting hematopoietic prostaglandin D synthase (HPGDS) may alleviate inflammation and decrease muscle necrosis. We tested our novel HPGDS inhibitor, PK007, in the mdx mouse model of DMD. Our results show that hindlimb grip strength was two-fold greater in the PK007-treated mdx group, compared to untreated mdx mice, and displayed similar muscle strength to strain control mice (C57BL/10ScSn). Histological analyses showed a decreased percentage of regenerating muscle fibers (~20% less) in tibialis anterior (TA) and gastrocnemius muscles and reduced fibrosis in the TA muscle in PK007-treated mice. Lastly, we confirmed that the DMD blood biomarker, muscle creatine kinase activity, was also reduced by ~50% in PK007-treated mdx mice. We conclude that our HPGDS inhibitor, PK007, has effectively reduced muscle inflammation and fibrosis in a DMD mdx mouse model.
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6

Spaulding, Hannah R., Tiffany Quindry, Kayleen Hammer, John C. Quindry, and Joshua T. Selsby. "Nutraceutical and pharmaceutical cocktails did not improve muscle function or reduce histological damage in D2-mdx mice." Journal of Applied Physiology 127, no. 4 (October 1, 2019): 1058–66. http://dx.doi.org/10.1152/japplphysiol.00162.2019.

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Progressive muscle injury and weakness are hallmarks of Duchenne muscular dystrophy. We showed previously that quercetin (Q) partially protected dystrophic limb muscles from disease-related injury. As quercetin activates PGC-1α through Sirtuin-1, an NAD+-dependent deacetylase, the depleted NAD+ in dystrophic skeletal muscle may limit quercetin efficacy; hence, supplementation with the NAD+ donor, nicotinamide riboside (NR), may facilitate quercetin efficacy. Lisinopril (Lis) protects skeletal muscle and improves cardiac function in dystrophin-deficient mice; therefore, it was included in this study to evaluate the effects of lisinopril used with quercetin and NR. Our purpose was to determine the extent to which Q, NR, and Lis decreased dystrophic injury. We hypothesized that Q, NR, or Lis alone would improve muscle function and decrease histological injury and when used in combination would have additive effects. Muscle function of 11-mo-old DBA (healthy), D2-mdx (dystrophin-deficient), and D2-mdx mice was assessed after treatment with Q, NR, and/or Lis for 7 mo. To mimic typical pharmacology of patients with Duchenne muscular dystrophy, a group was treated with prednisolone (Pred) in combination with Q, NR, and Lis. At 11 mo of age, dystrophin deficiency decreased specific tension and tetanic force in the soleus and extensor digitorum longus muscles and was not corrected by any treatment. Dystrophic muscle was more sensitive to contraction-induced injury, which was partially offset in the QNRLisPred group, whereas fatigue was similar between all groups. Treatments did not decrease histological damage. These data suggest that treatment with Q, NR, Lis, and Pred failed to adequately maintain dystrophic limb muscle function or decrease histological damage. NEW & NOTEWORTHY Despite a compelling rationale and previous evidence to the contrary in short-term investigations, quercetin, nicotinamide riboside, or Lisinopril, alone or in combination, failed to restore muscle function or decrease histological injury in dystrophic limb muscle from D2-mdx mice after long-term administration. Importantly, we also found that in the D2-mdx model, an emerging and relatively understudied model of Duchenne muscular dystrophy dystrophin deficiency caused profound muscle dysfunction and histopathology in skeletal muscle.
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7

Martins-Bach, A., E. Araujo, B. Matot, Y. Fromes, P. Baudin, I. Richard, and P. Carlier. "Nuclear magnetic resonance relaxometry characterization of D2-mdx mice." Neuromuscular Disorders 27 (October 2017): S124. http://dx.doi.org/10.1016/j.nmd.2017.06.120.

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8

Ward, Christopher W., Frederick Sachs, Ernest D. Bush, and Thomas M. Suchyna. "GsMTx4-D provides protection to the D2.mdx mouse." Neuromuscular Disorders 28, no. 10 (October 2018): 868–77. http://dx.doi.org/10.1016/j.nmd.2018.07.005.

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9

Pandeya, Sarbesh R., Janice A. Nagy, Daniela Riveros, Carson Semple, Rebecca S. Taylor, Benjamin Sanchez, and Seward B. Rutkove. "Relationships between in vivo surface and ex vivo electrical impedance myography measurements in three different neuromuscular disorder mouse models." PLOS ONE 16, no. 10 (October 29, 2021): e0259071. http://dx.doi.org/10.1371/journal.pone.0259071.

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Electrical impedance myography (EIM) using surface techniques has shown promise as a means of diagnosing and tracking disorders affecting muscle and assessing treatment efficacy. However, the relationship between such surface-obtained impedance values and pure muscle impedance values has not been established. Here we studied three groups of diseased and wild-type (WT) animals, including a Duchenne muscular dystrophy model (the D2-mdx mouse), an amyotrophic lateral sclerosis (ALS) model (the SOD1 G93A mouse), and a model of fat-related atrophy (the db/db diabetic obese mouse), performing hind limb measurements using a standard surface array and ex vivo measurements on freshly excised gastrocnemius muscle. A total of 101 animals (23 D2-mdx, 43 ALS mice, 12 db/db mice, and corresponding 30 WT mice) were studied with EIM across a frequency range of 8 kHz to 1 MHz. For both D2-mdx and ALS models, moderate strength correlations (Spearman rho values generally ranging from 0.3–0.7, depending on the impedance parameter (i.e., resistance, reactance and phase) were obtained. In these groups of animals, there was an offset in frequency with impedance values obtained at higher surface frequencies correlating more strongly to impedance values obtained at lower ex vivo frequencies. For the db/db model, correlations were comparatively weaker and strongest at very high and very low frequencies. When combining impedance data from all three disease models together, moderate correlations persisted (with maximal Spearman rho values of 0.45). These data support that surface EIM data reflect ex vivo muscle tissue EIM values to a moderate degree across several different diseases, with the highest correlations occurring in the 10–200 kHz frequency range. Understanding these relationships will prove useful for future applications of the technique of EIM in the assessment of neuromuscular disorders.
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10

English, Katherine G., Andrea L. Reid, Adrienne Samani, Gerald J. F. Coulis, S. Armando Villalta, Christopher J. Walker, Sharon Tamir, and Matthew S. Alexander. "Next-Generation SINE Compound KPT−8602 Ameliorates Dystrophic Pathology in Zebrafish and Mouse Models of DMD." Biomedicines 10, no. 10 (September 26, 2022): 2400. http://dx.doi.org/10.3390/biomedicines10102400.

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Duchenne muscular dystrophy (DMD) is a progressive, X-linked childhood neuromuscular disorder that results from loss-of-function mutations in the DYSTROPHIN gene. DMD patients exhibit muscle necrosis, cardiomyopathy, respiratory failure, and loss of ambulation. One of the major driving forces of DMD disease pathology is chronic inflammation. The current DMD standard of care is corticosteroids; however, there are serious side effects with long-term use, thus identifying novel anti-inflammatory and anti-fibrotic treatments for DMD is of high priority. We investigated the next-generation SINE compound, KPT−8602 (eltanexor) as an oral therapeutic to alleviate dystrophic symptoms. We performed pre-clinical evaluation of the effects of KPT−8602 in DMD zebrafish (sapje) and mouse (D2-mdx) models. KPT−8602 improved dystrophic skeletal muscle pathologies, muscle architecture and integrity, and overall outcomes in both animal models. KPT−8602 treatment ameliorated DMD pathology in D2-mdx mice, with increased locomotor behavior and improved muscle histology. KPT−8602 altered the immunological profile of the dystrophic mice, and reduced circulating osteopontin serum levels. These findings demonstrate KPT−8602 as an effective therapeutic in DMD through by promotion of an anti-inflammatory environment and overall improvement of DMD pathological outcomes.
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11

Putten, Maaike, Kayleigh Putker, Maurice Overzier, W. A. Adamzek, Svetlana Pasteuning-Vuhman, Jaap J. Plomp, and Annemieke Aartsma-Rus. "Natural disease history of the D2‐mdx mouse model for Duchenne muscular dystrophy." FASEB Journal 33, no. 7 (April 2019): 8110–24. http://dx.doi.org/10.1096/fj.201802488r.

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12

Kennedy, Tahnee L., Simon Guiraud, Ben Edwards, Sarah Squire, Lee Moir, Arran Babbs, Guy Odom, et al. "Micro-utrophin Improves Cardiac and Skeletal Muscle Function of Severely Affected D2/mdx Mice." Molecular Therapy - Methods & Clinical Development 11 (December 2018): 92–105. http://dx.doi.org/10.1016/j.omtm.2018.10.005.

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13

Spaulding, H. R., T. Quindry, J. C. Quindry, and J. T. Selsby. "Nutraceutical and pharmaceutical cocktails did not preserve diaphragm muscle function or reduce muscle damage in D2‐mdx mice." Experimental Physiology 105, no. 6 (May 19, 2020): 989–99. http://dx.doi.org/10.1113/ep087887.

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14

Pandeya, Sarbesh R., Janice A. Nagy, Daniela Riveros, Carson Semple, Rebecca S. Taylor, Marie Mortreux, Benjamin Sanchez, Kush Kapur, and Seward B. Rutkove. "Estimating myofiber cross‐sectional area and connective tissue deposition with electrical impedance myography: A study in D2 ‐ mdx mice." Muscle & Nerve 63, no. 6 (April 7, 2021): 941–50. http://dx.doi.org/10.1002/mus.27240.

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15

Ramos, Sofhia V., Meghan C. Hughes, Luca J. Delfinis, Catherine A. Bellissimo, and Christopher G. R. Perry. "Mitochondrial bioenergetic dysfunction in the D2.mdx model of Duchenne muscular dystrophy is associated with microtubule disorganization in skeletal muscle." PLOS ONE 15, no. 10 (October 1, 2020): e0237138. http://dx.doi.org/10.1371/journal.pone.0237138.

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16

Hamamura, Kengo, Yuya Yoshida, Kosuke Oyama, Junhao Li, Shimpei Kawano, Kimiko Inoue, Keiko Toyooka, et al. "Hematopoietic Prostaglandin D Synthase Is Increased in Mast Cells and Pericytes in Autopsy Myocardial Specimens from Patients with Duchenne Muscular Dystrophy." International Journal of Molecular Sciences 25, no. 3 (February 3, 2024): 1846. http://dx.doi.org/10.3390/ijms25031846.

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The leading cause of death for patients with Duchenne muscular dystrophy (DMD), a progressive muscle disease, is heart failure. Prostaglandin (PG) D2, a physiologically active fatty acid, is synthesized from the precursor PGH2 by hematopoietic prostaglandin D synthase (HPGDS). Using a DMD animal model (mdx mice), we previously found that HPGDS expression is increased not only in injured muscle but also in the heart. Moreover, HPGDS inhibitors can slow the progression of muscle injury and cardiomyopathy. However, the location of HPGDS in the heart is still unknown. Thus, this study investigated HPGDS expression in autopsy myocardial samples from DMD patients. We confirmed the presence of fibrosis, a characteristic phenotype of DMD, in the autopsy myocardial sections. Additionally, HPGDS was expressed in mast cells, pericytes, and myeloid cells of the myocardial specimens but not in the myocardium. Compared with the non-DMD group, the DMD group showed increased HPGDS expression in mast cells and pericytes. Our findings confirm the possibility of using HPGDS inhibitor therapy to suppress PGD2 production to treat skeletal muscle disorders and cardiomyopathy. It thus provides significant insights for developing therapeutic drugs for DMD.
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Bush, E., C. Ward, T. Suchyna, F. Sacks, M. Blaustein, and D. Escolar. "AT-300, a calcium modulator, improves muscle force production and decreases muscle degeneration in D2-mdx model of Duchenne muscular dystrophy." Neuromuscular Disorders 27 (October 2017): S192. http://dx.doi.org/10.1016/j.nmd.2017.06.358.

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18

Menuet, A., S. Buono, A. Robé, S. Chhor, L. Eyler, J. Becker, S. Colombo, and B. Cowling. "P.121 Dnm2 reduction combined with dystrophin re-expression ameliorates the myopathic phenotype observed in the D2-mdx model of Duchenne muscular dystrophy." Neuromuscular Disorders 32 (October 2022): S99. http://dx.doi.org/10.1016/j.nmd.2022.07.237.

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19

Cernisova, Viktorija, Ngoc Lu-Nguyen, Jessica Trundle, Shan Herath, Alberto Malerba, and Linda Popplewell. "Microdystrophin Gene Addition Significantly Improves Muscle Functionality and Diaphragm Muscle Histopathology in a Fibrotic Mouse Model of Duchenne Muscular Dystrophy." International Journal of Molecular Sciences 24, no. 9 (May 3, 2023): 8174. http://dx.doi.org/10.3390/ijms24098174.

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Duchenne muscular dystrophy (DMD) is a rare neuromuscular disease affecting 1:5000 newborn males. No cure is currently available, but gene addition therapy, based on the adeno-associated viral (AAV) vector-mediated delivery of microdystrophin transgenes, is currently being tested in clinical trials. The muscles of DMD boys present significant fibrotic and adipogenic tissue deposition at the time the treatment starts. The presence of fibrosis not only worsens the disease pathology, but also diminishes the efficacy of gene therapy treatments. To gain an understanding of the efficacy of AAV-based microdystrophin gene addition in a relevant, fibrotic animal model of DMD, we conducted a systemic study in juvenile D2.mdx mice using the single intravenous administration of an AAV8 system expressing a sequence-optimized murine microdystrophin, named MD1 (AAV8-MD1). We mainly focused our study on the diaphragm, a respiratory muscle that is crucial for DMD pathology and that has never been analyzed after treatment with AAV-microdystrophin in this mouse model. We provide strong evidence here that the delivery of AAV8-MD1 provides significant improvement in body-wide muscle function. This is associated with the protection of the hindlimb muscle from contraction-induced damage and the prevention of fibrosis deposition in the diaphragm muscle. Our work corroborates the observation that the administration of gene therapy in DMD is beneficial in preventing muscle fibrosis.
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Mázala, Davi A. G., Ravi Hindupur, Young Jae Moon, Fatima Shaikh, Iteoluwakishi H. Gamu, Dhruv Alladi, Georgiana Panci, et al. "Altered muscle niche contributes to myogenic deficit in the D2-mdx model of severe DMD." Cell Death Discovery 9, no. 1 (July 4, 2023). http://dx.doi.org/10.1038/s41420-023-01503-0.

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AbstractLack of dystrophin expression is the underlying genetic basis for Duchenne muscular dystrophy (DMD). However, disease severity varies between patients, based on specific genetic modifiers. D2-mdx is a model for severe DMD that exhibits exacerbated muscle degeneration and failure to regenerate even in the juvenile stage of the disease. We show that poor regeneration of juvenile D2-mdx muscles is associated with an enhanced inflammatory response to muscle damage that fails to resolve efficiently and supports the excessive accumulation of fibroadipogenic progenitors (FAPs), leading to increased fibrosis. Unexpectedly, the extent of damage and degeneration in juvenile D2-mdx muscle is significantly reduced in adults, and is associated with the restoration of the inflammatory and FAP responses to muscle injury. These improvements enhance regenerative myogenesis in the adult D2-mdx muscle, reaching levels comparable to the milder B10-mdx model of DMD. Ex vivo co-culture of healthy satellite cells (SCs) with juvenile D2-mdx FAPs reduces their fusion efficacy. Wild-type juvenile D2 mice also manifest regenerative myogenic deficit and glucocorticoid treatment improves their muscle regeneration. Our findings indicate that aberrant stromal cell responses contribute to poor regenerative myogenesis and greater muscle degeneration in juvenile D2-mdx muscles and reversal of this reduces pathology in adult D2-mdx muscle, identifying these responses as a potential therapeutic target for the treatment of DMD.
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Rosen, Grace, Kennedy Whitley, Alexander ReyesNegron, Nicolas Berger, Jared Lourie, Riley Cleverdon, Val Fajardo, and Kai Zou. "Impaired mitochondrial quality control in skeletal muscles from C57 and D2 mdx model of Duchenne Muscular Dystrophy." Physiology 38, S1 (May 2023). http://dx.doi.org/10.1152/physiol.2023.38.s1.5732496.

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Mitochondrial dysfunction is an early pathological feature of Duchenne muscular dystrophy (DMD) and precedes myopathy. Balanced mitochondrial quality control (e.g., fission, fusion, biogenesis, autophagy, and mitophagy) is essential to maintain the overall mitochondrial health and skeletal muscle function. DBA/2J mdx (D2- mdx) has emerged as a more relevant mouse model of DMD as it more closely mirrors early stage of DMD pathology in humans than the C57BL/10 mdx (C57 -mdx) model. The purpose of this study was to determine whether the expression of proteins responsible for mitochondrial quality control were dysregulated in skeletal muscles from these two mouse models of DMD. We hypothesized that the expression of protein markers of mitochondrial fission and mitophagy would be higher, while markers of mitochondrial fusion would be lower in both models of DMD with greater alterations in D2- mdx mice. 8-10-week-old male C57 -mdx and D2- mdx mice, and their respective wildtype (WT) mice were used in this study. Muscle strength was measured using hang wire test. Gastrocnemius muscles were collected for immunoblot analysis to assess mitochondrial quality control proteins. Hang wire impulse, an indicator of muscle strength, was significantly lower in both models of DMD in comparison to their WT controls (main effect of mdx, P = 0.01). Regarding mitochondrial fission, while there was no difference in protein expression and phosphorylation (Ser 616) of Dynamin-Related Protein 1 (Drp1) between any groups, mitochondrial fission 1 protein (Fis1) was markedly higher in skeletal muscles from both models of DMD when compared to WT controls (main effect of mdx, P=0.0001). Greater expression of Fis1 was observed in D2- mdx than C57- mdx when compared to their respective WT controls (~5.7-fold vs. 3.8-fold). Furthermore, mitochondrial fusion marker Mitofusion 1 (Mfn1) was significantly lower in both models of DMD (main effect of mdx, P=0.029), however, it appears to be mainly driven by the reduction in D2-mdx (mdx x strain interaction, P=0.019). No difference of Mfn1 expression was found in C57-mdx mice. Finally, expression of protein markers of mitochondrial biogenesis (PGC1 a) and autophagy (LC3B) were higher in both models of DMD when compared to their respective WT controls (main effect of mdx, P=0.0001 and P=0.001, respectively). In conclusion, these data suggest that there is dysregulated mitochondrial dynamics towards pro-fission state in skeletal muscle from mdx mice with an exacerbated effect in D2- mdx model, which may contribute to the muscle weakness phenotype associated with DMD This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
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Rosen, H. Grace, Nicolas Berger, Shantel Hodge, Atsutaro Fujishiro, Jared Lourie, Vrusti Kapadia, and Kai Zou. "Inhibiting Mitochondrial Fission Protein Drp1 Enhances Mitochondrial Structure, Attenuates Lipid Peroxidation, and Improves Muscle Strength in D2-mdx Mice." Physiology 39, S1 (May 2024). http://dx.doi.org/10.1152/physiol.2024.39.s1.2399.

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Duchenne Muscular Dystrophy (DMD) is the most severe muscular dystrophy manifested by progressive muscle wasting and weakness. Mitochondrial dysfunction and reactive oxygen species (ROS) accumulation are early pathological features of DMD and precede myopathy. A fine balance of mitochondrial dynamics (fission and fusion) is crucial to maintain mitochondrial function and skeletal muscle health. We recently reported excessive activation of Dynamin-Related Protein 1 (Drp1)-mediated mitochondrial fission in two animal models of DMD. Mitochondrial fission inhibitor‐1 (Mdivi‐1) is an effective pharmacological inhibitor of Drp1-mediated mitochondrial fission and has been shown benefits in numerous diseases. The objective of the study was to test whether Mdivi-1 could improve skeletal muscle mitochondrial structure, function and muscle strength in D2- mdx mouse model of DMD. Methods: 9-10-week-old male D2- mdx mice were treated with either Mdivi-1 (I.P., 40 mg/kg BW, mdx/Mdivi-1) or vehicle (2%DMSO in PBS, mdx/VEH) for 5 weeks. D2-wildtype mice treated with vehicle (WT/VEH) were used as the control (n=8/group). Muscle strength was measured using a grip strength meter. Mitochondria were isolated from quad muscles collected 24 hours after the last injection to measure mitochondrial respiration. Transmission Electron Microscopy was used to image mitochondrial structure. Gastrocnemius muscles were collected for immunoblot analysis. Results: Grip strength was significantly lower in muscles from D2- mdx mice compared to WT controls (P = 0.01) but was improved in mdx+Mdivi-1 mice (P = 0.05). Mitochondrial fission protein markers, Drp1(Ser616) phosphorylation and Fis1 were markedly higher in skeletal muscles from mdx/VEH than WT/VEH (P= 0.009 and 0.001) but were attenuated in mdx/Mdivi-1 mice (P = 0.041 and 0.1), indicating a rebalance of mitochondrial dynamics. This rebalance subsequently led to improvement in skeletal muscle mitochondrial structure in mdx/Mdivi-1 mice, with evidence of lower numbers of damaged mitochondria and reduced circularity (P = 0.005 and 0.038). Although not statistically significant, ADP and FCCP-stimulated mitochondrial respiration were enhanced by 93.8% and 92.4% in mdx+Mdivi-1 mice compared to mdx/VEH. In addition, lipid peroxidation marker, 4-HNE was significantly higher in mdx/VEH group in comparison to WT/VEH group (P = <0.0001), but was attenuated in mdx/Mdivi-1 mice (P = 0.08). Conclusion: These data demonstrate that inhibition of Drp1-mediated mitochondrial fission is effective in improving muscular strength in D2- mdx mice, which is at least partly due to enhanced mitochondrial dynamics, structure and attenuated lipid peroxidation. Mdivi-1 may be a viable treatment for DMD. National Institute of Health (R15DK131512). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
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23

Bellissimo, Catherine A., Luca J. Delfinis, Meghan C. Hughes, Patrick C. Turnbull, Shivam Gandhi, Sara N. DiBenedetto, Fasih A. Rahman, et al. "Mitochondrial creatine sensitivity is lost in the D2.mdx model of Duchenne muscular dystrophy and rescued by the mitochondrial-enhancing compound Olesoxime." American Journal of Physiology-Cell Physiology, January 23, 2023. http://dx.doi.org/10.1152/ajpcell.00377.2022.

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Duchenne muscular dystrophy (DMD) is associated with distinct mitochondrial stress responses. Here, we aimed to determine whether the prospective mitochondrial-enhancing compound Olesoxime prevents early-stage mitochondrial stress in limb and respiratory muscle from D2.mdx mice using a proof-of-concept short-term regimen spanning 10-28 days of age. As mitochondrial-cytoplasmic energy transfer occurs via ATP- or phosphocreatine-dependent phosphate shuttling, we assessed bioenergetics with or without creatine in vitro. We observed that disruptions in Complex I-supported respiration and H2O2 emission in D2.mdx quadriceps and diaphragm were amplified by creatine demonstrating mitochondrial creatine insensitivity manifests ubiquitously and early in this model. Olesoxime selectively rescued or maintained creatine sensitivity in both muscles, independent of the abundance of respiration-related mitochondrial proteins or mitochondrial creatine kinase cysteine oxidation in quadriceps. Mitochondrial calcium retention capacity and glutathione were altered in a muscle-specific manner in D2.mdx but were generally unchanged by Olesoxime. Treatment reduced serum creatine kinase (muscle damage) and preserved cage hang-time, microCT-based volumes of lean compartments including whole body, hindlimb and bone, recovery of diaphragm force after fatigue, and cross-sectional area of diaphragm type IIX fibre, but reduced type I fibres in quadriceps. Grip strength, voluntary wheel-running and fibrosis were unaltered by Olesoxime. In summary, locomotor and respiratory muscle mitochondrial creatine sensitivities are lost during early stages in D2.mdx mice but are preserved by short-term treatment with Olesoxime in association with specific indices of muscle quality suggesting early myopathy in this model is at least partially attributed to mitochondrial stress.
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24

Marcella, Bianca, Briana Hockey, Luc Wasilewicz, Sophie Hamstra, Mia Geromella, Rebecca MacPherson, and Val Andrew Fajardo. "Voluntary wheel running and lithium supplementation promotes fatigue resistance, fat oxidation, and improves insulin tolerance in D2 mdx mice." Physiology 38, S1 (May 2023). http://dx.doi.org/10.1152/physiol.2023.38.s1.5731889.

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BACKGROUND: Duchenne muscular dystrophy (DMD) is an X-linked disorder characterized by progressive muscle wasting and premature death. Many DMD patients will also exhibit signs of metabolic dysfunction such as insulin resistance that predisposes them to type 2 diabetes and worsened cardiovascular disease. Most treatments for DMD aim to lower muscle inflammation and improve strength, however, none have addressed the complication of insulin resistance. The current standard of treatment is corticosteroids, which prolongs ambulation, however, chronic use increases susceptibility to obesity, insulin resistance, and type 2 diabetes. It is well-established that regular aerobic exercise enhances insulin sensitivity. Further, we have recently found that inhibiting glycogen synthase kinase 3 with lithium (Li), a known insulin mimetic, improves force production and fatigue resistance in wildtype (WT) mice. Here, we tested whether voluntary wheel running (VWR) and Li supplementation, together, could improve whole-body fatigue, metabolism, and insulin sensitivity in the DBA/2J (D2) mdx mouse model of DMD. METHODS: 5-week old male D2 WT and mdx mice were separated into four groups: WT, mdx sedentary (SED), mdx VWR, and mdx Li+VWR (n=11/group). The mdx VWR and mdx Li+VWR mice had unlimited access to a cagewheel, and mdx Li+VWR mice were given a low dose of Li (50 mg/kg/day) via their drinking water throughout the study. A treadmill time-to-fatigue test was performed to assess whole-body fatigue. Mice were housed for 48-hours in metabolic cages to measure energy expenditure. Glucose handling was measured using glucose and insulin tolerance tests. RESULTS: As expected, WT mice had ~2-fold greater total cage activity compared to all mdx groups. When examining cagewheel distance, we found that mdx Li+VWR mice ran half the total distance in kilometres than mdx VWR mice (39.1 ± 9.6 km vs. 74.8 ± 13.6 km). Despite this, VWR with and without Li improved whole-body fatigue as only mdx SED mice (22.8 ± 0.9 min) had a shorter time to exhaustion than WT mice (32.6 ± 0.9 min). All mdx groups had higher energy expenditure than WT mice, suggestive of a hypermetabolic phenotype. When examining the respiratory exchange ratio (RER) among mdx mice, mdxLi+VWR (0.87) mice had a lower RER than mdx SED mice (0.91), indicative of enhanced fat oxidation. Glucose tolerance was equally impaired among mdx groups compared to WT mice. However, insulin tolerance was notably improved in mdx VWR and mdx Li+VWR mice, with a greater improvement observed in the mdx Li+VWR mice. CONCLUSION: Despite running less than mdx VWR mice, mdx Li+VWR mice had enhanced fatigue resistance, fat utilization, and insulin sensitivity, suggesting Li may be a viable treatment to improve muscle and metabolic function in mdx mice. CIHR CRC (Tier II) to VAF This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
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25

Geromella, Mia, Bianca Marcella, Briana Hockey, Rene Vandenboom, and Val Fajardo. "Voluntary wheel running and lithium supplementation improves muscle force production without altering SERCA function in the D2 mdx mouse." Physiology 38, S1 (May 2023). http://dx.doi.org/10.1152/physiol.2023.38.s1.5730580.

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Background: Duchenne muscular dystrophy (DMD) is an X-linked recessive muscle wasting disease that, with no cure, leads to early mortality (30-40 years of age). Previous studies have shown that voluntary wheel running can mitigate disease pathology and improve muscle contractility in the preclinical mdx mouse model. We have shown that treating wild-type (WT) mice with a low dose of lithium, a natural inhibitor of glycogen synthase kinase 3, enhanced soleus (SOL) and extensor digitorum longus (EDL) muscle contractility. Our objectives were to test our hypothesis of whether combining VWR with low dose lithium supplementation could provide further benefits to muscle contractility in DBA/2J mdx mice – a model that displays far worse disease severity compared with the traditional C57BL/10 mdx mouse. We also examined if this combined intervention could improve muscle calcium regulation in muscle by assessing sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) function as we have recently shown that SERCA function is drastically impaired in D2 mdx mice, which could also contribute to deficits in muscle force production. Methods: Young (5-6 week old) male D2 WT and mdx mice were ordered from Jackson Laboratory. D2 mdx mice were assigned into each of the following conditions: sedentary ( mdxSED), voluntary wheel running ( mdxVWR), or VWR+lithium chloride ( mdxVWR+Li). The VWR groups were given access to a cagewheel for a total of 6 weeks, and the mdxVWR+Li group were provided a low dose of LiCl (50 mg/kg/day) via drinking water for the entire duration of the study. After 6 weeks, all mice were euthanized and the SOL and EDL muscles were subjected to force-frequency curve analysis (1-160 Hz). SERCA function was assessed by performing SERCA activity assays and a Ca2+ uptake assay. Results: In the SOL, the combined effect of lithium and VWR improved specific force production to near WT levels across submaximal and maximal frequencies. Specific force production in the mdxVWR+Li group was significantly greater compared to the mdxSED group at all stimulation frequencies. Rate of SOL force development was significantly lower in all mdx groups compared to WT. However, rate of relaxation was only significantly reduced (vs. WT) within the mdxSED group, suggesting that VWR and VWR+Li improved relaxation. This could not be explained by any changes in SERCA function. In the EDL, specific force was significantly (p<0.001) reduced across mdx groups compared to WT; however, of all mdx groups, the mdxVWR+Li produced the most force and was significantly different compared to mdxVWR at 80 and 160 Hz. Rates of force development and relaxation were all slower in all mdx groups compared to WT, and there were no differences in SERCA activity. Conclusions: Combining lithium supplementation with VWR improved SOL and EDL force production in the D2 mdx mouse without any changes to SERCA function. V.A.F is a Tier 2 Canada Research Chair in Muscle Plasticity and Tissue-Remodelling. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
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26

Krishna, Swathy, Hannah R. Spaulding, Tiffany S. Quindry, Matthew B. Hudson, John C. Quindry, and Joshua T. Selsby. "Indices of Defective Autophagy in Whole Muscle and Lysosome Enriched Fractions From Aged D2-mdx Mice." Frontiers in Physiology 12 (July 9, 2021). http://dx.doi.org/10.3389/fphys.2021.691245.

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Duchenne muscular dystrophy (DMD) is a fatal, progressive muscle disease caused by the absence of functional dystrophin protein. Previous studies in mdx mice, a common DMD model, identified impaired autophagy with lysosomal insufficiency and impaired autophagosomal degradation as consequences of dystrophin deficiency. Thus, we hypothesized that lysosomal abundance would be decreased and degradation of autophagosomes would be impaired in muscles of D2-mdx mice. To test this hypothesis, diaphragm and gastrocnemius muscles from 11 month-old D2-mdx and DBA/2J (healthy) mice were collected. Whole muscle protein from diaphragm and gastrocnemius muscles, and protein from a cytosolic fraction (CF) and a lysosome-enriched fraction (LEF) from gastrocnemius muscles, were isolated and used for western blotting. Initiation of autophagy was not robustly activated in whole muscle protein from diaphragm and gastrocnemius, however, autophagosome formation markers were elevated in dystrophic muscles. Autophagosome degradation was impaired in D2-mdx diaphragms but appeared to be maintained in gastrocnemius muscles. To better understand this muscle-specific distinction, we investigated autophagic signaling in CFs and LEFs from gastrocnemius muscles. Within the LEF we discovered that the degradation of autophagosomes was similar between groups. Further, our data suggest an expanded, though impaired, lysosomal pool in dystrophic muscle. Notably, these data indicate a degree of muscle specificity as well as model specificity with regard to autophagic dysfunction in dystrophic muscles. Stimulation of autophagy in dystrophic muscles may hold promise for DMD patients as a potential therapeutic, however, it will be critical to choose the appropriate model and muscles that most closely recapitulate findings from human patients to further develop these therapeutics.
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27

Bellissimo, Catherine A., Shivam Gandhi, Laura N. Castellani, Mayoorey Murugathasan, Luca J. Delfinis, Arshdeep Thuhan, Madison C. Garibotti, et al. "The slow-release adiponectin analogue ALY688-SR modifies early-stage disease development in the D2.mdx mouse model of Duchenne muscular dystrophy." American Journal of Physiology-Cell Physiology, December 25, 2023. http://dx.doi.org/10.1152/ajpcell.00638.2023.

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Fibrosis is associated with respiratory and limb muscle atrophy in Duchenne muscular dystrophy (DMD). Current standard of care partially delays the progression of this myopathy but there remains an unmet need to develop additional therapies. Adiponectin receptor agonism has emerged as a possible therapeutic target to lower inflammation and improve metabolism in mdx mouse models of DMD but the degree to which fibrosis and atrophy are prevented remain unknown. Here, we demonstrate that the recently developed slow-release peptidomimetic adiponectin analogue, ALY688-SR, remodels the diaphragm of D2. mdx mice treated from days 7-28 of age during early stages of disease. ALY688-SR also lowered IL-6mRNA but increased IL-6 and TGF-β1 protein contents in diaphragm, suggesting dynamic inflammatory remodeling. ALY688-SR alleviated mitochondrial redox stress by decreasing complex I-stimulated H2O2 emission. Treatment also lowered in vitro diaphragm force production in diaphragm suggesting a complex relationship between adiponectin receptor activity, muscle remodeling and force generating properties during the very early stages of disease progression in D2. mdx mice. In tibialis anterior, the modest fibrosis at this young age was not altered by treatment, and atrophy was not apparent at this young age. These results demonstrate that short-term treatment of ALY688-SR in young D2. mdx mice partially prevents fibrosis and fibre type-specific atrophy and lowered force production in the more disease-apparent diaphragm in relation to lower mitochondrial redox stress and heterogeneous responses in certain inflammatory markers. These diverse muscle responses to adiponectin receptor agonism in early stages of DMD serve as a foundation for further mechanistic investigations.
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28

Licandro, Simonetta Andrea, Luca Crippa, Roberta Pomarico, Raffaella Perego, Gianluca Fossati, Flavio Leoni, and Christian Steinkühler. "The pan HDAC inhibitor Givinostat improves muscle function and histological parameters in two Duchenne muscular dystrophy murine models expressing different haplotypes of the LTBP4 gene." Skeletal Muscle 11, no. 1 (July 22, 2021). http://dx.doi.org/10.1186/s13395-021-00273-6.

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Abstract Background In the search of genetic determinants of Duchenne muscular dystrophy (DMD) severity, LTBP4, a member of the latent TGF-β binding protein family, emerged as an important predictor of functional outcome trajectories in mice and humans. Nonsynonymous single-nucleotide polymorphisms in LTBP4 gene associate with prolonged ambulation in DMD patients, whereas an in-frame insertion polymorphism in the mouse LTBP4 locus modulates disease severity in mice by altering proteolytic stability of the Ltbp4 protein and release of transforming growth factor-β (TGF-β). Givinostat, a pan-histone deacetylase inhibitor currently in phase III clinical trials for DMD treatment, significantly reduces fibrosis in muscle tissue and promotes the increase of the cross-sectional area (CSA) of muscles in mdx mice. In this study, we investigated the activity of Givinostat in mdx and in D2.B10 mice, two mouse models expressing different Ltbp4 variants and developing mild or more severe disease as a function of Ltbp4 polymorphism. Methods Givinostat and steroids were administrated for 15 weeks in both DMD murine models and their efficacy was evaluated by grip strength and run to exhaustion functional tests. Histological examinations of skeletal muscles were also performed to assess the percentage of fibrotic area and CSA increase. Results Givinostat treatment increased maximal normalized strength to levels that were comparable to those of healthy mice in both DMD models. The effect of Givinostat in both grip strength and exhaustion tests was dose-dependent in both strains, and in D2.B10 mice, Givinostat outperformed steroids at its highest dose. The in vivo treatment with Givinostat was effective in improving muscle morphology in both mdx and D2.B10 mice by reducing fibrosis. Conclusion Our study provides evidence that Givinostat has a significant effect in ameliorating both muscle function and histological parameters in mdx and D2.B10 murine models suggesting a potential benefit also for patients with a poor prognosis LTBP4 genotype.
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29

Young, Laura V., William Morrison, Craig Campbell, Emma C. Moore, Michel G. Arsenault, Athan G. Dial, Sean Ng, et al. "Loss of dystrophin expression in skeletal muscle is associated with senescence of macrophages and endothelial cells." American Journal of Physiology-Cell Physiology, May 12, 2021. http://dx.doi.org/10.1152/ajpcell.00397.2020.

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Cellular senescence is the irreversible arrest of normally dividing cells and is driven by cell cycle inhibitory proteins such as p16, p21 and p53. When cells enter senescence, they secrete a host of proinflammatory factors known as the senescence associated secretory phenotype which has deleterious effects on surrounding cells and tissues. Little is known of the role of senescence in Duchenne Muscular Dystrophy (DMD), the fatal X-linked neuromuscular disorder typified by chronic inflammation, extracellular matrix remodeling and a progressive loss in muscle mass and function. Here, we demonstrate using C57-mdx (8-week-old) and D2-mdx mice (4-week and 8-week-old), two mouse models of DMD, that cells displaying canonical markers of senescence are found within skeletal muscle. 8-week-old D2-mdx mice, which display severe muscle pathology, had greater numbers of senescent cells associated with areas of inflammation which were mostly Cdkn1a-positive macrophages while in C57-mdx muscle, senescent populations were endothelial cells and macrophages localized to newly regenerated myofibers. Interestingly, this pattern was similar to cardiotoxin (CTX)-injured wildtype (WT) muscle which experienced a transient senescent response. Dystrophic muscle demonstrated significant upregulations in senescence pathway genes (Cdkn1a (p21), Cdkn2a (p16INK4A), Trp53 (p53)) which correlated with the quantity of SA-b-Gal-positive cells. These results highlight an underexplored role for cellular senescence in murine dystrophic muscle.
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30

Aartsma-Rus, Annemieke, Maaike van Putten, Paola Mantuano, and Annamaria De Luca. "On the use of D2.B10-Dmdmdx/J (D2.mdx) Versus C57BL/10ScSn-Dmdmdx/J (mdx) Mouse Models for Preclinical Studies on Duchenne Muscular Dystrophy: A Cautionary Note from Members of the TREAT-NMD Advisory Committee on Therapeutics." Journal of Neuromuscular Diseases, October 31, 2022, 1–4. http://dx.doi.org/10.3233/jnd-221547.

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The C57BL/10ScSn-Dmdmdx/J (mdx) mouse model has been used by researchers for decades as a model to study pathology of and develop therapies for Duchenne muscular dystrophy. However, the model is relatively mildly affected compared to the human situation. Recently, the D2.B10-Dmdmdx/J (D2.mdx) mouse model was suggested as a more severely affected and therefore better alternative. While the pathology of this model is indeed more pronounced early in life, it is not progressive, and increasing evidence suggest that it actually partially resolves with age. As such, caution is needed when using this model. However, as preclinical experts of the TREAT-NMD advisory committee for therapeutics (TACT), we frequently encounter study designs that underestimate this caveat. We here provide context for how to best use the two models for preclinical studies at the current stage of knowledge.
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31

Pandeya, Sarbesh, Benjamin Sanchez, Janice A. Nagy, and Seward B. Rutkove. "Combining electromyographic and electrical impedance data sets through machine learning: A study in D2‐mdx and wild‐type mice." Muscle & Nerve, September 2, 2023. http://dx.doi.org/10.1002/mus.27963.

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AbstractIntroduction/AimsNeedle impedance‐electromyography (iEMG) assesses the active and passive electrical properties of muscles concurrently by using a novel needle with six electrodes, two for EMG and four for electrical impedance myography (EIM). Here, we assessed an approach for combining multifrequency EMG and EIM data via machine learning (ML) to discriminate D2‐mdx muscular dystrophy and wild‐type (WT) mouse skeletal muscle.MethodsiEMG data were obtained from quadriceps of D2‐mdx mice, a muscular dystrophy model, and WT animals. EIM data were collected with the animals under deep anesthesia and EMG data collected under light anesthesia, allowing for limited spontaneous movement. Fourier transformation was performed on the EMG data to provide power spectra that were sampled across the frequency range using three different approaches. Random forest‐based, nested ML was applied to the EIM and EMG data sets separately and then together to assess healthy versus disease category classification using a nested cross‐validation procedure.ResultsData from 20 D2‐mdx and 20 WT limbs were analyzed. EIM data fared better than EMG data in differentiating healthy from disease mice with 93.1% versus 75.6% accuracy, respectively. Combining EIM and EMG data sets yielded similar performance as EIM data alone with 92.2% accuracy.DiscussionWe have demonstrated an ML‐based approach for combining EIM and EMG data obtained with an iEMG needle. While EIM‐EMG in combination fared no better than EIM alone with this data set, the approach used here demonstrates a novel method of combining the two techniques to characterize the full electrical properties of skeletal muscle.
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32

Donen, Graham, Nadia Milad, and Pascal Bernatchez. "Humanization of the mdx Mouse Phenotype for Duchenne Muscular Dystrophy Modeling: A Metabolic Perspective." Journal of Neuromuscular Diseases, August 10, 2023, 1–10. http://dx.doi.org/10.3233/jnd-230126.

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Duchenne muscular dystrophy (DMD) is a severe form of muscular dystrophy (MD) that is characterized by early muscle wasting and lethal cardiorespiratory failure. While the mdx mouse is the most common model of DMD, it fails to replicate the severe loss of muscle mass and other complications observed in patients, in part due to the multiple rescue pathways found in mice. This led to several attempts at improving DMD animal models by interfering with these rescue pathways through double transgenic approaches, resulting in more severe phenotypes with mixed relevance to the human pathology. As a growing body of literature depicts DMD as a multi-system metabolic disease, improvements in mdx-based modeling of DMD may be achieved by modulating whole-body metabolism instead of muscle homeostasis. This review provides an overview of the established dual-transgenic approaches that exacerbate the mild mdx phenotype by primarily interfering with muscle homeostasis and highlights how advances in DMD modeling coincide with inducing whole-body metabolic changes. We focus on the DBA2/J strain-based D2.mdx mouse with heightened transforming growth factor (TGF)-β signaling and the dyslipidemic mdx/apolipoprotein E (mdx/ApoE) knock-out (KO) mouse, and summarize how these novel models emulate the metabolic changes observed in DMD.
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33

Donen, Graham, Nadia Milad, and Pascal Bernatchez. "Humanization of the mdx Mouse Phenotype for Duchenne Muscular Dystrophy Modeling: A Metabolic Perspective." Journal of Neuromuscular Diseases, August 10, 2023, 1–10. http://dx.doi.org/10.3233/jnd-230126.

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Duchenne muscular dystrophy (DMD) is a severe form of muscular dystrophy (MD) that is characterized by early muscle wasting and lethal cardiorespiratory failure. While the mdx mouse is the most common model of DMD, it fails to replicate the severe loss of muscle mass and other complications observed in patients, in part due to the multiple rescue pathways found in mice. This led to several attempts at improving DMD animal models by interfering with these rescue pathways through double transgenic approaches, resulting in more severe phenotypes with mixed relevance to the human pathology. As a growing body of literature depicts DMD as a multi-system metabolic disease, improvements in mdx-based modeling of DMD may be achieved by modulating whole-body metabolism instead of muscle homeostasis. This review provides an overview of the established dual-transgenic approaches that exacerbate the mild mdx phenotype by primarily interfering with muscle homeostasis and highlights how advances in DMD modeling coincide with inducing whole-body metabolic changes. We focus on the DBA2/J strain-based D2.mdx mouse with heightened transforming growth factor (TGF)-β signaling and the dyslipidemic mdx/apolipoprotein E (mdx/ApoE) knock-out (KO) mouse, and summarize how these novel models emulate the metabolic changes observed in DMD.
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34

Stec, Michael J., Qi Su, Christina Adler, Lance Zhang, David R. Golann, Naveen P. Khan, Lampros Panagis, et al. "A cellular and molecular spatial atlas of dystrophic muscle." Proceedings of the National Academy of Sciences 120, no. 29 (July 6, 2023). http://dx.doi.org/10.1073/pnas.2221249120.

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Asynchronous skeletal muscle degeneration/regeneration is a hallmark feature of Duchenne muscular dystrophy (DMD); however, traditional -omics technologies that lack spatial context make it difficult to study the biological mechanisms of how asynchronous regeneration contributes to disease progression. Here, using the severely dystrophic D2-mdx mouse model, we generated a high-resolution cellular and molecular spatial atlas of dystrophic muscle by integrating spatial transcriptomics and single-cell RNAseq datasets. Unbiased clustering revealed nonuniform distribution of unique cell populations throughout D2-mdx muscle that were associated with multiple regenerative timepoints, demonstrating that this model faithfully recapitulates the asynchronous regeneration observed in human DMD muscle. By probing spatiotemporal gene expression signatures, we found that propagation of inflammatory and fibrotic signals from locally damaged areas contributes to widespread pathology and that querying expression signatures within discrete microenvironments can identify targetable pathways for DMD therapy. Overall, this spatial atlas of dystrophic muscle provides a valuable resource for studying DMD disease biology and therapeutic target discovery.
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35

Copeland, Emily, Bianca Marcella, Bradley Baranowski, Ahmad Mohammad, Shawn Beaudette, Rebecca MacPherson, and Val Fajardo. "Combined effects of lithium supplementation and exercise on memory in the D2 mdx mouse." Physiology 38, S1 (May 2023). http://dx.doi.org/10.1152/physiol.2023.38.s1.5731878.

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Introduction: Duchenne muscular dystrophy (DMD) is an X-linked muscle wasting disease that occurs in 1 in 3500 boys. With muscular deficits, approximately one third of patients experience cognitive difficulties, including memory loss. Recently, it was found that DBA/2J (D2) mdx mice present with memory deficits and an increased presence of Alzheimer’s disease (AD)-like markers. A common contributor to AD pathology is glycogen synthase kinase 3 (GSK3), which promotes the production of amyloid beta (Aβ) via an increase in beta secretase 1 (BACE1) content and activity. Additionally, GSK3β has been shown to limit the expression and activation of the sarco(endo)plasmic reticulum calcium (Ca2+) ATPase (SERCA), which also pathologically contributes to AD via increased free cytosolic Ca2+ and neurodegeneration. Aerobic exercise in preclinical models of AD have been shown to inhibit GSK3 and reduce BACE1 activity; however, its effects on the mdx brain remains unknown. Furthermore, whether GSK3 in combination with exercise can provide additional cognitive benefits for the mdx mouse remains unknown. Here, we examined the effects of 6 weeks of voluntary wheel running (VWR) with and without the supplementation of low dose lithium, a natural GSK3 inhibitor. We hypothesized that aerobic exercise combined with lithium supplementation (VWR+Li) would provide the most cognitive benefit via a reduction in BACE1 activity and an enhancement in SERCA activity. Methods: 5-6 weeks old mice were separated into four groups: 1) wild-type (WT) healthy controls, 2 ) mdx sedentary, 3 ) mdx VWR, and 4 ) mdx VWR+Li (50 mg/kg/day lithium chloride via drinking water). An automated novel object recognition test (NORT) was conducted on the 5th week of training. At the time of euthanasia, hippocampal and prefrontal cortex (PFC) samples were collected. All samples were subjected to BACE1 and SERCA activity assays. Results: Automated NORT analysis showed that the VWR+Li mdx mice had higher investigation times compared to the mdx sedentary group ( p < 0.05), four hours post-training, similar to WT healthy controls. In the hippocampus, the mdx VWR+Li group had lower BACE1 activity compared to the mdx sedentary group; however, VWR alone could not elicit a similar effect, despite the fact VWR+Li ran less than VWR alone ( p < 0.05). Furthermore, maximal SERCA activity was higher in the VWR+Li mdx group compared to all other groups ( p < 0.05). In the PFC, no differences in BACE1 nor SERCA activity were found between the experimental groups. Conclusions: The combined therapy of VWR and lithium supplementation in mdx mice attenuated memory deficits, which was associated with lowered BACE1 activity and elevated maximal SERCA activity in the hippocampus. This work reveals exercise in conjunction with GSK3β inhibition as a potential therapeutic for DMD. CIHR and CRC to VAF. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
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36

Krishna, Swathy, Hannah R. Spaulding, James E. Koltes, John C. Quindry, Rudy J. Valentine, and Joshua T. Selsby. "Indicators of increased ER stress and UPR in aged D2-mdx and human dystrophic skeletal muscles." Frontiers in Physiology 14 (April 25, 2023). http://dx.doi.org/10.3389/fphys.2023.1152576.

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Duchenne muscular dystrophy (DMD) is a progressive muscle disease that results in muscle wasting, wheelchair dependence, and eventual death due to cardiac and respiratory complications. In addition to muscle fragility, dystrophin deficiency also results in multiple secondary dysfunctions, which may lead to the accumulation of unfolded proteins causing endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). The purpose of this investigation was to understand how ER stress and the UPR are modified in muscle from D2-mdx mice, an emerging DMD model, and from humans with DMD. We hypothesized that markers of ER stress and the UPR are upregulated in D2-mdx and human dystrophic muscles compared to their healthy counterparts. Immunoblotting in diaphragms from 11-month-old D2-mdx and DBA mice indicated increased ER stress and UPR in dystrophic diaphragms compared to healthy, including increased relative abundance of ER stress chaperone CHOP, canonical ER stress transducers ATF6 and pIRE1α S724, and transcription factors that regulate the UPR such as ATF4, XBP1s, and peIF2α S51. The publicly available Affymetrix dataset (GSE38417) was used to analyze the expression of ER stress and UPR-related transcripts and processes. Fifty-eight upregulated genes related to ER stress and the UPR in human dystrophic muscles suggest pathway activation. Further, based on analyses using iRegulon, putative transcription factors that regulate this upregulation profile were identified, including ATF6, XBP1, ATF4, CREB3L2, and EIF2AK3. This study adds to and extends the emerging knowledge of ER stress and the UPR in dystrophin deficiency and identifies transcriptional regulators that may be responsible for these changes and be of therapeutic interest.
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Wasilewicz, Luc, Sophie Hamstra, Briana Hockey, Jessica Braun, Bianca Marcella, Ryan Baranowski, Rebecca MacPherson, and Val Fajardo. "Investigating the effects of thermoneutral housing on skeletal and cardiac muscle function in D2 mdx mice." Physiology 38, S1 (May 2023). http://dx.doi.org/10.1152/physiol.2023.38.s1.5792468.

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Since its discovery, the mdx mouse has been the foundation for research on Duchenne muscular dystrophy (DMD) and its potential therapies. Although, nearly all studies using mdx mice as an experimental model have been conducted under “standard” lab conditions using room (22C) instead of thermoneutral (TN, 30C) temperature housing. Room temperature (RT) is a mild cold stress to mice, causing metabolic adaptations that can confound experimental results, limiting their interpretation and translation to humans. This study investigated the effects of housing temperature on whole-body metabolism and skeletal and cardiac muscle function in the mdx mouse. To this end, 20 D2 mdx mice (age 5 weeks, n = 10 per group) were housed at RT and TN for 10 weeks. Metabolic cage analysis demonstrated that TN housed mdx mice displayed significantly decreased VO2 consumption and reduced food intake that was likely due to lowered daily energy expenditure. TN housed mice also had significantly lower respiratory exchange ratio values, indicative of increased fat metabolism. However, there were no differences in body mass or composition (i.e., % lean and fat mass). Treadmill-to-fatigue experiments revealed no differences in exercise performance. Furthermore, ex vivo muscle contractility analysis displayed no differences in extensor digitorum longus or soleus specific force generation between TN and RT housed mice. Analysis of cardiac structure/function demonstrated that TN housed mdx mice exhibited a reduction in cardiac output, which we attributed to diastolic dysfunction. While ejection fraction and fractional shortening were not different among the two groups, TN housing led to a significant reduction in end diastolic volume (EDV) and left ventricle internal diameter (diastole, LVID;d), as well as increased relative wall thickness (diastole, RWT;d) compared to RT housed mice. Though isovolumic relaxation time was prolonged in TN-housed mice, this did not reach statistical significance. Taken together, our results demonstrate that TN housing had minimal effects on skeletal muscle contractility, but did lead to signs of diastolic dysfunction in young mdx mice. Future studies will examine the effects of TN housing in aged mdx mice, when systolic dysfunction occurs, as well as any influence of TN housing on the efficacy of potential muscle wasting therapeutics. Overall, our results support the growing literature that highlights the importance of selecting the appropriate housing temperature when studying metabolism or muscle wasting conditions in mice. NSERC This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
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Dort, Junio, Zakaria Orfi, Melissa Fiscaletti, Philippe M. Campeau, and Nicolas A. Dumont. "Gpr18 agonist dampens inflammation, enhances myogenesis, and restores muscle function in models of Duchenne muscular dystrophy." Frontiers in Cell and Developmental Biology 11 (August 14, 2023). http://dx.doi.org/10.3389/fcell.2023.1187253.

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Introduction: Muscle wasting in Duchenne Muscular Dystrophy is caused by myofiber fragility and poor regeneration that lead to chronic inflammation and muscle replacement by fibrofatty tissue. Our recent findings demonstrated that Resolvin-D2, a bioactive lipid derived from omega-3 fatty acids, has the capacity to dampen inflammation and stimulate muscle regeneration to alleviate disease progression. This therapeutic avenue has many advantages compared to glucocorticoids, the current gold-standard treatment for Duchenne Muscular Dystrophy. However, the use of bioactive lipids as therapeutic drugs also faces many technical challenges such as their instability and poor oral bioavailability.Methods: Here, we explored the potential of PSB-KD107, a synthetic agonist of the resolvin-D2 receptor Gpr18, as a therapeutic alternative for Duchenne Muscular Dystrophy.Results and discussion: We showed that PSB-KD107 can stimulate the myogenic capacity of patient iPSC-derived myoblasts in vitro. RNAseq analysis revealed an enrichment in biological processes related to fatty acid metabolism, lipid biosynthesis, small molecule biosynthesis, and steroid-related processes in PSB-KD107-treated mdx myoblasts, as well as signaling pathways such as Peroxisome proliferator-activated receptors, AMP-activated protein kinase, mammalian target of rapamycin, and sphingolipid signaling pathways. In vivo, the treatment of dystrophic mdx mice with PSB-KD107 resulted in reduced inflammation, enhanced myogenesis, and improved muscle function. The positive impact of PSB-KD107 on muscle function is similar to the one of Resolvin-D2. Overall, our findings provide a proof-of concept that synthetic analogs of bioactive lipid receptors hold therapeutic potential for the treatment of Duchenne Muscular Dystrophy.
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Boccanegra, Brigida, Paola Mantuano, Elena Conte, Alessandro Giovanni Cerchiara, Lisamaura Tulimiero, Raffaella Quarta, Erika Caputo, et al. "LKB1 signaling is altered in skeletal muscle of a Duchenne muscular dystrophy mouse model." Disease Models & Mechanisms 16, no. 7 (July 1, 2023). http://dx.doi.org/10.1242/dmm.049930.

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ABSTRACT The potential role of liver kinase B1 (LKB1) in the altered activation of the master metabolic and epigenetic regulator adenosine monophosphate-activated protein kinase (AMPK) in Duchenne muscular dystrophy has not been investigated so far. Hence, we analyzed both gene and protein levels of LKB1 and its related targets in gastrocnemius muscles of adult C57BL/10 mdx mice and D2 mdx mice, a model with a more severe dystrophic phenotype, as well as the sensitivity of the LKB1–AMPK pathway to AMPK activators, such as chronic exercise. Our data show, for the first time, a reduction in the levels of LKB1 and accessory proteins, MO25 and STRADα, in both mdx strains versus the respective wild type, which was further impaired by exercise, in parallel with a lack of further phosphorylation of AMPK. The AMPK-like kinase salt-inducible kinase (SIK) and class II histone deacetylases, along with expression of the HDAC target gene Mef2c, were also altered, supporting an impairment of LKB1-SIK-class II histone deacetylase signaling. Our results demonstrate that LKB1 may be involved in dystrophic progression, paving the way for future preclinical studies.
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40

Quindry, John C., Tiffany S. Quindry, Kathryn Tiemessen, and Joshua T. Selsby. "Cardiac, respiratory, and physical activity profiles in young D2‐mdx dystrophic mice." FASEB Journal 32, S1 (April 2018). http://dx.doi.org/10.1096/fasebj.2018.32.1_supplement.583.3.

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41

Copeland, Emily, Kennedy Whitley, Riley Cleverdon, Bradley Baranowski, Daniel Marko, Rebecca MacPherson, David Allison, and Val Fajardo. "Kynurenine Metabolism in the D2 mdx Mouse: A Muscle‐to‐Brain Connection." FASEB Journal 35, S1 (May 2021). http://dx.doi.org/10.1096/fasebj.2021.35.s1.02762.

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42

Chrzanowski, Stephen Mark, Janice A. Nagy, Sarbesh Pandeya, and Seward B. Rutkove. "Electrical Impedance Myography Correlates with Functional Measures of Disease Progression in D2-mdx Mice and Boys with Duchenne Muscular Dystrophy." Journal of Neuromuscular Diseases, November 25, 2022, 1–10. http://dx.doi.org/10.3233/jnd-210787.

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Background: Sensitive, objective, and longitudinal outcome measures applicable to both pre-clinical and clinical interventions are needed to assess muscle health in Duchenne muscular dystrophy (DMD). Electrical impedance myography (EIM) has the potential to non-invasively measure disease progression in mice and boys with DMD. Objective: We sought to evaluate how electrical impedance values (i.e., phase, reactance, and resistance) correlate to established measures of disease in both D2-mdx and wild type (WT) mice and boys with and without DMD. Methods: Histological, functional, and EIM data collected from previous studies of WT and D2-mdx mice at 6, 13, 21 and 43 weeks of age were reanalyzed. In parallel, previously collected functional outcome measures and EIM values were reanalyzed from boys with and without DMD at four different age groups from 2 to 14 years old. Results: In mice, disease progression as detected by histological, functional, and EIM measures, was appreciable over this time period and grip strength best correlated to longitudinal phase and reactance impedance values. In boys, disease progression quantified through commonly utilized functional outcome measures was significant and longitudinal phase demonstrated the strongest correlation with functional outcome measures. Conclusion: Similar changes in EIM values, specifically in longitudinal reactance and phase, were found to show significant correlations to functional measures in both mice and boys. Thus, EIM demonstrates applicability in both pre-clinical and clinical settings and can be used as a safe, non-invasive, and longitudinal proxy biomarker to assess muscle health in DMD.
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Kendra, Jacob, Alexandra Naman, Richard Brow, Steven Segal, and Aaron Morton. "TRIM Enhances Dystrophic Muscle Function 70 Days Post Treatment." Physiology 39, S1 (May 2024). http://dx.doi.org/10.1152/physiol.2024.39.s1.937.

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Background: Duchenne Muscular Dystrophy (DMD) is associated with limb muscle dysfunction caused by progressive weakness and degeneration of skeletal muscle. Current FDA-approved therapeutic strategies are less effective than originally hoped. Our alternative approach was to develop a novel biomaterial, Time Release Ion Matrix (TRIM), shown to release angiogenic ions and enhance muscle structure and function at 14 days post injection (dpi) in dystrophic (D2. mdx) mice. However, the long-term effects of TRIM are unknown. Hypothesis: At 70 days post injection in D2. mdx mice TRIM will: 1) enhance isometric force and myofiber cross-sectional area (CSA) of the tibialis anterior (TA) muscle; and 2) promote vascular endothelial growth factor (VEGF) availability and muscle vascularity. Methods: The right and left TA of adult male D2. mdx mice (n=6-7, age 5 months) were injected with saline alone (control) or 250 μg of TRIM suspended in saline. At 70 dpi, the left TA was isolated for in situ muscle force measurements and histological analysis; the right TA was frozen for biochemical analysis. Muscle cross-sections were immunostained for laminin (myofiber borders), DAPI (nuclei), and CD31 (endothelial cells). An ELISA for VEGF was performed on homogenates of frozen muscles. Results: TA’s injected with TRIM increased peak isometric force (means ± SE: TRIM 70.9 ± 1.8 g; Saline, 65.9 ± 1.1 g; P= 0.04). TRIM-treated TA’s had a 2.2-fold increase in relative frequency of myofibers >1000 μm2 (TRIM, 31.8 ± 3.7%; Saline, 14.4 ± 1.9%; P= 0.001), and reduced the frequency of myofibers <400 μm2 by 32% (TRIM, 38.6% ± 2.8; Saline, 56.5% ± 3.5; P= 0.001). DAPI staining revealed a 50% increase in central myonuclei indicative of regenerated myofibers (TRIM, 30.2 ± 1.7%; Saline, 20.2 ± 1.3%; P=0.0006). Microvessel area (CD31 staining; μm2) was 2.1-fold greater in treated TA’s (TRIM, 135.6 ± 8.7 μm2; Saline, 63.6 ± 4.5 μm2; P=0.0001). In muscle homogenates, TRIM increased [VEGF] (TRIM, 139 ± 10%; Saline, 100 ± 6%; P= 0.009) Conclusion: Results support the hypothesis that 70 days following injection of TRIM into the TA of dystrophic mice, muscle force and myofiber CSA are enhanced. Moreover, TRIM enhances VEGF with increased vascularity, suggesting that the angiogenic effects of TRIM complement those on myogenesis and contractile function towards restoring muscle structure and function in DMD. University of Missouri Coulter Biomedical Accelerator (SSS), Texas A&M Department of Kinesiology and Sport Management (ABM). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
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Naman, Alexandra, Jacob Kendra, Richard Brow, Steven Segal, and Aaron Morton. "TRIM Enhances Angiogenesis in Dystrophic Muscle 140 Days Post Treatment." Physiology 39, S1 (May 2024). http://dx.doi.org/10.1152/physiol.2024.39.s1.947.

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Background: Duchenne Muscular Dystrophy (DMD) causes limb muscle dysfunction and impaired mobility while promoting ischemia in effected muscles. For treatment, we developed a novel biomaterial, Time Release Ion Matrix (TRIM), that promotes angiogenesis and enhances muscle structure and function in dystrophic (D2. mdx) mice at 14- and 70-days post injection (dpi). Whether TRIM remains effective at 140 dpi is unknown. Hypothesis: At 140 dpi in D2. mdx mice TRIM will: 1) enhance isometric force and myofiber cross-sectional area (CSA) of the tibialis anterior (TA) muscle; and 2) stimulate angiogenic growth factors and increase vascularity. Methods: The right and left TA of adult male D2. mdx mice (male, n=7-8, age 7 months) were injected with saline alone (control) or 250 μg of TRIM suspended in saline. At 140 dpi, the left TA muscle was isolated for in situ muscle force measurements and histological analysis; the right TA was frozen for biochemical analysis. Muscle cross-sections were immunostained for laminin (myofiber borders), DAPI (nuclei), and CD31 (endothelial cells). Vascular endothelial growth factor (VEGF) ELISA and immunoblots were performed on muscle homogenates. Results: No difference in peak isometric force was recorded between groups at 140 dpi (means ± SE: TRIM, 65.4 ± 2.7g; Saline, 62.7 ± 1.5g; P= 0.34). TRIM enhanced the relative frequency of myofibers >1000 μm2 by 27% vs. saline (TRIM, 56 ± 2%; Saline, 44 ± 3%; P= 0.006). DAPI staining revealed a 36% increase in central nuclei indicating myofiber regeneration (TRIM, 30.0 ± 1.7%; Saline, 22.0% ± 2.5; P=0.02). Microvessel area (CD31 staining, μm2) was 2.5-fold greater in treated TA’s (TRIM, 131 ± 12 μm2; Saline, 53 ± 6 μm2, P=0.0001). In muscle homogenates, TRIM had no effect on [VEGF] (TRIM, 102 ± 5%; Saline, 100 ± 4%; P= 0.79), while STAT3 activation was greater (TRIM, 129 ± 11%; Saline, 100 ± 7%; P= 0.04). Conclusion: At 140 days following injection of TRIM into the TA muscle of dystrophic mice, peak isometric force was unchanged while myofiber CSA was enhanced. Furthermore, TRIM promotes angiogenic growth factors and muscle vascularity, which should promote the ability to sustain physical activity. University of Missouri Coulter Biomedical Accelerator (SSS), American Physiological Society SURF (AGN), Texas A&M Department of Kinesiology and Sport Management (ABM). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
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Wohlgemuth, Ross, Sathvik Sriram, Kyle Henricson, Daryl Dinh, Sarah Brashear, and Lucas Smith. "Collagen fibers within skeletal muscle extracellular matrix dynamically change their alignment in a stretch-dependent fashion." Physiology 39, S1 (May 2024). http://dx.doi.org/10.1152/physiol.2024.39.s1.809.

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Collagen fiber architecture within the skeletal muscle extracellular matrix (ECM) contributes to muscle passive mechanical properties. There is evidence that collagen fibers change their alignment during muscle lengthening (stretching). Thus, the goal of this study was to characterize the dynamic changes of collagen fiber alignment in the muscle ECM during muscle stretching, and to assess the relationship between dynamic collagen re-alignment and muscle passive mechanics. We hypothesized that collagen fibers increase their alignment as the muscle is stretched, and that increased collagen alignment in stretched muscle is correlated to higher elastic stiffness. Extensor digitorum longus (EDL), soleus, and diaphragm muscles were collected from wildtype (WT) and D2.mdx (MDX) mice of 48-52 weeks of age. Muscles underwent a series of twitches to determine the optimum length (Lo) for isometric contraction, and then were decellularized to isolate the muscle ECM. Decellularized muscles (DCMs) were then mechanically tested using a series of stress-relaxation tests at 5% increments from 85% to 115% length relative to Lo. Elastic stiffness was measured as the slope of the tangent line on the stress-strain curve following stress-relaxation. Following mechanical testing, DCMs were imaged using second harmonic generation microscopy to visualize collagen alignment across the range of lengths used in mechanical testing. Collagen alignment was reported as an alignment index on a scale of 0 (perfect unalignment) to 1 (perfect alignment). We found that MDX diaphragm DCMs were less stiff than WT (WT: 910.2±586.7, MDX: 238±168.7, p=0.0041), but there were no significant differences in stiffness between WT and MDX EDL and soleus DCMs. We also observed a significant effect of stretch on collagen alignment in all DCMs tested (Diaphragm: p=0.0071, EDL: p=0.0004, soleus: p<0.0001). Interestingly, the collagen fibers of the epimysium, the outermost layer of the muscle ECM, were more aligned in WT diaphragm DCMs than in MDX (WT 85%: 0.672±.14, MDX 85%: 0.344±0.16, p=0.0027; WT 115%: 0.783±0.04, MDX 115%: 0.480±0.19, p=0.0036). Finally, we found a significant positive correlation between the alignment and elastic stiffness at 110% Lo across all DCMs (p=0.0038, R2=0.1713). These data indicate that collagen fibers dynamically re-align as muscle is stretched. Additionally, increased collagen fiber alignment is associated with higher passive stiffness in the decellularized muscle ECM. Overall, we find that dynamic architectural changes in the muscle ECM contribute to passive mechanical behavior during a muscle stretch. This work was supported by a grant from the NIH NIAMS (R01-AR079545). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
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46

Hayward, Grant, M. Caceres, Emily Copeland, Bradley Baranowski, Ahmad Mohammad, Kennedy Whitley, Val Fajardo, and Rebecca MacPherson. "Characterization of Alzheimer's Disease‐like Neuropathology in Duchenne Muscular Dystrophy Using the D2 mdx Mouse Model." FASEB Journal 35, S1 (May 2021). http://dx.doi.org/10.1096/fasebj.2021.35.s1.02834.

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47

Cleverdon, Riley, Kennedy Whitley, Daniel Marko, Rebecca MacPherson, and Val Fajardo. "Sarcoplasmic Reticulum Ca 2+ Handling in Gastrocnemius Muscles from 10‐week‐old C57 and D2‐ mdx Mice." FASEB Journal 35, S1 (May 2021). http://dx.doi.org/10.1096/fasebj.2021.35.s1.03200.

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48

Heezen, L. G. M., T. Abdelaal, M. van Putten, A. Aartsma-Rus, A. Mahfouz, and P. Spitali. "Spatial transcriptomics reveal markers of histopathological changes in Duchenne muscular dystrophy mouse models." Nature Communications 14, no. 1 (August 15, 2023). http://dx.doi.org/10.1038/s41467-023-40555-9.

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AbstractDuchenne muscular dystrophy is caused by mutations in the DMD gene, leading to lack of dystrophin. Chronic muscle damage eventually leads to histological alterations in skeletal muscles. The identification of genes and cell types driving tissue remodeling is a key step to developing effective therapies. Here we use spatial transcriptomics in two Duchenne muscular dystrophy mouse models differing in disease severity to identify gene expression signatures underlying skeletal muscle pathology and to directly link gene expression to muscle histology. We perform deconvolution analysis to identify cell types contributing to histological alterations. We show increased expression of specific genes in areas of muscle regeneration (Myl4, Sparc, Hspg2), fibrosis (Vim, Fn1, Thbs4) and calcification (Bgn, Ctsk, Spp1). These findings are confirmed by smFISH. Finally, we use differentiation dynamic analysis in the D2-mdx muscle to identify muscle fibers in the present state that are predicted to become affected in the future state.
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Whitley, Kennedy, Sophie Hamstra, Sebastian Silvera, and Val Fajardo. "Tideglusib inhibition of GSK3 promotes the oxidative muscle phenotype and reduces serum creatine kinase in D2 mdx mice." FASEB Journal 35, S1 (May 2021). http://dx.doi.org/10.1096/fasebj.2021.35.s1.02597.

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50

Hammers, David W., Cora C. Hart, Michael K. Matheny, Lillian A. Wright, Megan Armellini, Elisabeth R. Barton, and H. Lee Sweeney. "The D2.mdx mouse as a preclinical model of the skeletal muscle pathology associated with Duchenne muscular dystrophy." Scientific Reports 10, no. 1 (August 21, 2020). http://dx.doi.org/10.1038/s41598-020-70987-y.

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