Moderate exercise improves function and increases adiponectin in the mdx mouse model of muscular dystrophy

Zelikovich, Aaron S.; Quattrocelli, Mattia; Salamone, Isabella M.; Kuntz, Nancy L.; McNally, Elizabeth M.

doi:10.1038/s41598-019-42203-z

Cited by 37 publications

(19 citation statements)

References 39 publications

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“… 25 One of the key outcomes for gene therapy, therefore, should be the rescue of diaphragm function, as respiratory failure often leads to death. 25 In the absence of treatment, moderate treadmill exercise improves respiratory function in mdx-DBA/2J mice, 48 while in contrast, impaired diaphragm function in mdx mice after 52 weeks of running yielded an ∼60% decline compared to sedentary controls. 15 Treatment with microdystrophin in mdx mice at least partially rescued muscle strength and resistance to eccentric injury in both limb and diaphragm muscles.…”

Section: Discussionmentioning

confidence: 99%

Voluntary wheel running complements microdystrophin gene therapy to improve muscle function in mdx mice

Hamm

Fathalikhani

Bukovec

et al. 2021

Molecular Therapy - Methods & Clinical Development

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We tested the hypothesis that voluntary wheel running would complement microdystrophin gene therapy to improve muscle function in young mdx mice, a model of Duchenne muscular dystrophy. mdx mice injected with a single dose of AAV9-CK8-microdystrophin or vehicle at age 7 weeks were assigned to three groups: mdxRGT (run, gene therapy), mdxGT (no run, gene therapy), or mdx (no run, no gene therapy). Wild-type (WT) mice were assigned to WTR (run) and WT (no run) groups. WTR and mdxRGT performed voluntary wheel running for 21 weeks; remaining groups were cage active. Robust expression of microdystrophin occurred in heart and limb muscles of treated mice. mdxRGT versus mdxGT mice showed increased microdystrophin in quadriceps but decreased levels in diaphragm. mdx final treadmill fatigue time was depressed compared to all groups, improved in mdxGT, and highest in mdxRGT. Both weekly running distance (km) and final treadmill fatigue time for mdxRGT and WTR were similar. Remarkably, mdxRGT diaphragm power was only rescued to 60% of WT, suggesting a negative impact of running. However, potential changes in fiber type distribution in mdxRGT diaphragms could indicate an adaptation to trade power for endurance. Post-treatment in vivo maximal plantar flexor torque relative to baseline values was greater for mdxGT and mdxRGT versus all other groups. Mitochondrial respiration rates from red quadriceps fibers were significantly improved in mdxGT animals, but the greatest bioenergetic benefit was observed in the mdxRGT group. Additional assessments revealed partial to full functional restoration in mdxGT and mdxRGT muscles relative to WT. These data demonstrate that voluntary wheel running combined with microdystrophin gene therapy in young mdx mice improved whole-body performance, affected muscle function differentially, mitigated energetic deficits, but also revealed some detrimental effects of exercise. With microdystrophin gene therapy currently in clinical trials, these data may help us understand the potential impact of exercise in treated patients.

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Section: Discussionmentioning

confidence: 99%

Voluntary wheel running complements microdystrophin gene therapy to improve muscle function in mdx mice

Hamm

Fathalikhani

Bukovec

et al. 2021

Molecular Therapy - Methods & Clinical Development

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“…Replenishment of ApN by transgenesis mitigated the dystrophic phenotype by attenuating inflammation while improving regeneration, muscle function, and physical performance . Likewise, increasing serum ApN by moderate exercise was associated with improved muscle function in mdx mice . On the contrary, complete depletion of ApN levels greatly aggravated the phenotype .…”

Section: Discussionmentioning

confidence: 96%

AdipoRon, a new therapeutic prospect for Duchenne muscular dystrophy

Abou‐Samra

Selvais

Boursereau

et al. 2020

J cachexia sarcopenia muscle

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Background Adiponectin (ApN) is a hormone known to exhibit insulin-sensitizing, fat-burning, and anti-inflammatory properties in several tissues, including the skeletal muscle. Duchenne muscular dystrophy (DMD) is a devastating disease characterized by dystrophin deficiency with subsequent chronic inflammation, myofiber necrosis, and impaired regeneration. Previously, we showed that transgenic up-regulation of ApN could significantly attenuate the dystrophic phenotype in mdx mice (model of DMD). Recently, an orally active ApN receptor agonist, AdipoRon, has been identified. This synthetic small molecule has the advantage of being more easily produced and administrable than ApN. The aim of this study was to investigate the potential effects of AdipoRon on the dystrophic muscle. Methods Four-week-old mdx mice (n = 6-9 per group) were orally treated with AdipoRon (mdx-AR) for 8 weeks and compared with untreated (mdx) mice and to control (wild-type) mice. In vivo functional tests were carried out to measure the global force and endurance of mice. Ex vivo biochemical and molecular analyses were performed to evaluate the pathophysiology of the skeletal muscle. Finally, in vitro tests were conducted on primary cultures of healthy and DMD human myotubes. Results AdipoRon treatment mitigated oxidative stress (À30% to 45% for 4-hydroxy-2-nonenal and peroxiredoxin 3, P < 0.0001) as well as inflammation in muscles of mdx mice (À35% to 65% for interleukin 1 beta, tumour necrosis factor alpha, and cluster of differentiation 68, a macrophage maker, P < 0.0001) while increasing the anti-inflammatory cytokine, interleukin 10 (~5-fold, P < 0.0001). AdipoRon also improved the myogenic programme as assessed by a~2-fold rise in markers of muscle proliferation and differentiation (P < 0.01 or less vs. untreated mdx). Plasma lactate dehydrogenase and creatine kinase were reduced by 30-40% in mdx-AR mice, reflecting less sarcolemmal damage (P < 0.0001). When compared with untreated mdx mice, mdx-AR mice exhibited enhanced physical performance with an increase in both muscle force and endurance and a striking restoration of the running capacity during eccentric exercise. AdipoRon mainly acted through ApN receptor 1 by increasing AMP-activated protein kinase signalling, which led to repression of nuclear factor-kappa B, upregulation of utrophin (a dystrophin analogue), and a switch towards an oxidative and more resistant fibre phenotype. The effects of AdipoRon were then recapitulated in human DMD myotubes. Conclusions These results demonstrate that AdipoRon exerts several beneficial effects on the dystrophic muscle. This molecule could offer promising therapeutic prospect for managing DMD or other muscle and inflammatory disorders.

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“…Further, with age, mdx mice had greater diaphragm muscle atrophy and fibrosis, leading to increased respiratory impairment compared to WT mice [ 55 – 57 ]. Previous work assessing ventilatory function in mdx mice using WBP has been predominantly performed with males [ 58 – 60 ], with some studies pooling male and female mice [ 41 , 61 ], or with sex not reported [ 62 ]. This study is the first that we know of to report ventilatory function in only female mdx mice across ages.…”

Section: Discussionmentioning

confidence: 99%

Impact of estrogen deficiency on diaphragm and leg muscle contractile function in female mdx mice

et al. 2021

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Female carriers of Duchenne muscular dystrophy (DMD) presenting with DMD symptomology similar to males with DMD, such as skeletal muscle weakness and cardiomyopathy, are termed manifesting carriers. There is phenotypic variability among manifesting carriers including the age of onset, which can range from the first to fourth decade of life. In females, estrogen levels typically begin to decline during the fourth decade of life and estrogen deficiency contributes to loss of muscle strength and recovery of strength following injury. Thus, we questioned whether the decline of estrogen impacts the development of DMD symptoms in females. To address this question, we studied 6–8 month-old homozygous mdx female mice randomly assigned to a sham or ovariectomy (OVX) surgical group. In vivo whole-body plethysmography assessed ventilatory function and diaphragm muscle strength was measured in vitro before and after fatigue. Anterior crural muscles were analyzed in vivo for contractile function, fatigue, and in response to eccentric contraction (ECC)-induced injury. For the latter, 50 maximal ECCs were performed by the anterior crural muscles to induce injury. Body mass, uterine mass, hypoxia-hypercapnia ventilatory response, and fatigue index were analyzed by a pooled unpaired t-test. A two-way ANOVA was used to analyze ventilatory measurements. Fatigue and ECC-injury recovery experiments were analyzed by a two-way repeated-measures ANOVA. Results show no differences between sham and OVX mdx mice in ventilatory function, strength, or recovery of strength after fatigue in the diaphragm muscle or anterior crural muscles (p ≥ 0.078). However, OVX mice had significantly greater eccentric torque loss and blunted recovery of strength after ECC-induced injury compared to sham mice (p ≤ 0.019). Although the results show that loss of estrogen has minimal impact on skeletal muscle contractile function in female mdx mice, a key finding suggests that estrogen is important in muscle recovery in female mdx mice after injury.

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Moderate exercise improves function and increases adiponectin in the mdx mouse model of muscular dystrophy

Cited by 37 publications

References 39 publications

Voluntary wheel running complements microdystrophin gene therapy to improve muscle function in mdx mice

Voluntary wheel running complements microdystrophin gene therapy to improve muscle function in mdx mice

AdipoRon, a new therapeutic prospect for Duchenne muscular dystrophy

Impact of estrogen deficiency on diaphragm and leg muscle contractile function in female mdx mice

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