Abstract

Mutation to the dystrophin gene causes skeletal muscle weakness in patients with Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD). Deliberation continues regarding implications of prescribing exercise for these patients. The purpose of this study was to determine whether isometric resistance exercise (~10 tetanic contractions/session) improves skeletal muscle strength and histopathology in the mdx mouse model of DMD. Three isometric training sessions increased in vivo isometric torque (22%) and contractility rates (54%) of anterior crural muscles of mdx mice. Mice expressing a BMD-causing missense mutated dystrophin on the mdx background showed comparable increases in torque (22%), while wild-type mice showed less change (11%). Increases in muscle function occurred within 1 h and peaked 3 days posttraining; however, the adaptation was lost after 7 days unless retrained. Six isometric training sessions over 4 wk caused increased isometric torque (28%) and contractility rates (22-28%), reduced fibrosis, as well as greater uniformity of fiber cross-sectional areas, fewer embryonic myosin heavy-chain-positive fibers, and more satellite cells in tibialis anterior muscle compared with the contralateral untrained muscle. Ex vivo functional analysis of isolated extensor digitorum longus (EDL) muscle from the trained hindlimb revealed greater absolute isometric force, lower passive stiffness, and a lower susceptibility to eccentric contraction-induced force loss compared with untrained EDL muscle. Overall, these data support the concept that exercise training in the form of isometric tetanic contractions can improve contractile function of dystrophin-deficient muscle, indicating a potential role for enhancing muscle strength in patients with DMD and BMD. NEW & NOTEWORTHY We focused on adaptive responses of dystrophin-deficient mouse skeletal muscle to isometric contraction training and report that in the absence of dystrophin (or in the presence of a mutated dystrophin), strength and muscle histopathology are improved. Results suggest that the strength gains are associated with fiber hypertrophy, reduced fibrosis, increased number of satellite cells, and blunted eccentric contraction-induced force loss in vitro. Importantly, there was no indication that the isometric exercise training was deleterious to dystrophin-deficient muscle.

Highlights

  • Loss of dystrophin protein causes Duchenne muscular dystrophy (DMD) [31]

  • Between the 1960s and 1980s, clinical trials on patients with neuromuscular diseases showed that resistance-type exercise maintained or improved skeletal muscle strength, while finding no evidence for exacerbation of disease [38, 59, 64]

  • The effects of aerobic exercise on physical strength are being studied in ambulatory and nonambulatory boys with DMD (NCT03319030), and isometric resistance exercise on muscle strength and safety is being investigated in 7–10-yr-old boys with DMD (NCT02421523)

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Summary

Introduction

Loss of dystrophin protein causes Duchenne muscular dystrophy (DMD) [31]. Expression of a truncated and partially functional dystrophin protein causes the milder Becker muscular dystrophy (BMD). Other studies with the mdx mouse show that endurance types of exercise like swimming or running can result in adaptations that improve the dystrophin-deficient skeletal muscle phenotype [7, 12, 27, 28, 32, 43, 60]. The potential for skeletal muscle adaptations to be induced by resistance exercise training is even less clear, and a cautionary point of this type of exercise for patients with DMD is eccentric muscle contractions [3] This caution emanates from the use of maximal eccentric contractions in mdx mouse muscle showing high susceptibility of dystrophin-deficient skeletal muscle to force loss [48, 56].

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