BASIC & TRANSLATIONAL SCIENCE EFFECT OF VOLUNTARY PHYSICAL ACTIVITY INITIATED AT AGE 7 MONTHS ON SKELETAL HINDLIMB AND CARDIAC MUSCLE FUNCTION IN mdx MICE OF BOTH GENDERS ARNAUD FERRY, PhD, 1,2 RACHID BENCHAOUIR, PhD, 3 PIERRE JOANNE, PhD, 4 RACHEL A. PEAT, PhD, 5 NATHALIE MOUGENOT, PhD, 6 ONNIK AGBULUT, PhD, 4 and GILLIAN BUTLER-BROWNE, PhD 1 1 Universit e Pierre et Marie Curie-Paris 6, Sorbonne Universit es, UMR S794, INSERM, U974, CNRS UMR 7215, Institut de Myologie, Paris, France 2 Universite  Paris Descartes, Sorbonne Paris Cit e, Paris, France 3 Universit e de Versailles Saint Quentin en Yvelines, Inflammation et th erapeutiques, Montigny-le-Bretonneux, France 4 Universit e Pierre et Marie Curie 6, Sorbonne Universit es, UMR CNRS 8256, Biological Adaptation and Ageing, Paris, France 5 Universit e Pierre et Marie Curie-Paris 6, Sorbonne Universit es, UMR S956, INSERM, ICAN Institute for Cardiometabolism and Nutrition, Paris, France 6 Universit e Pierre et Marie Curie-Paris 6, Sorbonne Universit es, PECVM, Paris, France Accepted 9 February 2015 ABSTRACT: Introduction: The effects of voluntary activity initi- ated in adult mdx (C57BL/10ScSc-DMD mdx /J) mice on skeletal and cardiac muscle function have not been studied extensively. Methods: We studied the effects of 3 months of voluntary wheel running initiated at age 7 months on hindlimb muscle weakness, increased susceptibility to muscle contraction2induced injury, and left ventricular function in mdx mice. Results: We found that voluntary wheel running did not worsen the deficit in force- generating capacity and the force drop after lengthening contrac- tions in either mdx mouse gender. It increased the absolute max- imal force of skeletal muscle in female mdx mice. Moreover, it did not affect left ventricular function, structural heart dimensions, cardiac gene expression of inflammation, fibrosis, or remodeling markers. Conclusion: These results indicate that voluntary activ- ity initiated at age 7 months had no detrimental effects on skele- tal or cardiac muscles in either mdx mouse gender. Muscle Nerve 52: 788–794, 2015 The muscular dystrophies are a group of inherited muscle disorders, the most common of which is Duchenne muscular dystrophy (DMD). DMD is a degenerative disorder affecting both skeletal and cardiac muscles; it is caused by a deficiency in dys- trophin, a subsarcolemmal protein that plays a role in force transmission and sarcolemma stability. 1–4 Skeletal muscles from dystrophin-deficient mdx (C57BL/10ScSc-DMD mdx /J) mice, a widely used DMD mouse model, display weakness, that is, reduced specific maximal force (absolute maximal force generated relative to muscle cross-sectional area or weight). 5–9 mdx muscle is also more susceptible to damage caused by lengthening contractions (contrac- tion with stretch). For example, repeated lengthening contractions in fast-type muscles result in reduced maximal force (force drop) in fast-type muscle in mdx mice, but not wild-type mice. 5,9–11 These 2 dystro- phic features worsen with age and are more severe in male than female mdx mice. 9 Over the last few deca- des, several therapeutic approaches for replacing the defective dystrophin gene have been shown to be effective in ameliorating muscle weakness and reduc- ing susceptibility to lengthening contraction2in- duced damage in mdx mice. 12–14 However, until these therapies are clinically available, other interventions may be useful as interim measures. Voluntary activity to improve dystrophic hind- limb skeletal muscle characteristics is a promising potential therapy. Several voluntary activity2based studies have been conducted in mdx mice using free wheel running for durations from 3 weeks up to 13 months. 7,15–19 Studies have reported that vol- untary activity can increase specific maximal force in hindlimb muscles, although there are discrepan- cies concerning which muscles are improved or unchanged (e.g., soleus muscle vs. extensor digito- rum longus muscle). 15,16,19,20 Few investigations have evaluated the effect of voluntary activity on mdx muscle susceptibility to lengthening contrac- tion2induced damage. 15,21 One study showed that voluntary activity mitigates the force drop after lengthening contractions in mdx fast muscle, 21 whereas another study reported no change in the mixed-type soleus muscle. 15 However, the discrep- ancy is most likely explained by the fact that the mdx soleus muscle is equally as susceptible to lengthening contraction2induced damage as wild- type muscle. 11,22 The notion that activity could be beneficial to hindlimb muscles in mdx mice is also Abbreviations: DMD, Duchenne muscular dystrophy; EDV, left ventricle end-diastolic volume; EF, ejection fraction; ESV, end-systolic volume; FS, fractional shortening; IVS, interventricular septum; Lo, optimal muscle length; LV, left ventricle; LVEDD, left ventricle end-diastolic diameter; LVESD, left ventricle end-systolic diameter; LVPW, left ventricular posterior wall thickness; LVV, LV myocardial volume; Po, absolute maximal force; qPCR, quantitative polymerase chain reaction; sPo, specific maximal force; TA, tibialis anterior muscle Key words: cardiac muscle; function; mdx mouse; skeletal muscle; voluntary activity This study was supported by the Universit e Pierre et Marie Curie, CNRS, INSERM, University Paris Descartes, and the Association Franc ¸aise contre les Myopathies. Correspondence to: A. Ferry, G.H. Piti e-Salp^ etrie ` re, 47, boulevard de l’H^ opital, B^ atiment Babinski, INSERM U974, 75651 Paris cedex 13, France; e-mail: arnaud.ferry@upmc.fr V C 2015 Wiley Periodicals, Inc. Published online 20 February 2015 in Wiley Online Library (wileyonlinelibrary. com). DOI 10.1002/mus.24604 788 Physical Activity in mdx Mice MUSCLE & NERVE November 2015