Voluntary exercise improves muscle function and does not exacerbate muscle and heart pathology in aged Duchenne muscular dystrophy mice

Abstract

Duchenne muscular dystrophy is a severe muscle wasting disease, characterized by a severely reduced lifespan in which cardiomyopathy is one of the leading causes of death. Multiple therapies aiming at dystrophin restoration have been approved. It is anticipated that these therapies will maintain muscle function for longer and extend the ambulatory period, which in turn will increase the cardiac workload which could be detrimental for cardiac function. We investigated the effects of voluntary running exercise in combination with low dystrophin levels on function and pathology of skeletal muscle and heart. We divided 15.5-month old female mdx (no dystrophin), mdx-Xist Δhs (varying low dystrophin levels) and wild type mice (BL10-WT and Xist Δhs -WT) to either a sedentary or voluntary wheel running regime and assessed muscle function at 17.5 months of age. Thereafter, a cardiac MRI was obtained, and muscle and heart histopathology were assessed. We show that voluntary exercise is beneficial to skeletal muscle and heart function in dystrophic mice while not affecting muscle pathology. Low amounts of dystrophin further improve skeletal muscle and cardiac function. These findings suggest that voluntary exercise may be beneficial for skeletal muscle and heart in DMD patients, especially in conjunction with low amounts of dystrophin. key characteristic of cardiomyopathy is the dilated left ventricle, found in the majority of older DMD patients [3][4][5], while studies on right ventricular function are less coherent [6][7][8]. Early detection is challenging, since cardiac involvement does not always result into clinical symptoms due to exercise intolerance resulting from skeletal muscle weakness.Not only DMD patients, but also Becker muscular dystrophy (BMD) patients suffer from cardiac myopathy. BMD patients have in-frame mutations in the DMD gene leading to synthesis of reduced levels of truncated, but partially functional dystrophin proteins. Consequently, their muscle pathology is less severe than DMD patients. However, despite the expression of low dystrophin levels, about two thirds of BMD patients develop cardiomyopathy [9][10][11]. Similarly, DMD and BMD carriers, expressing 50% of dystrophin, also have an increased risk for cardiomyopathy [12,13].Currently there are two therapeutic strategies approved aimed to

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

“…Specifically, the mdx model in the DBA2J background is useful for examining cardiac phenotypes and this was seen in this work, as sedentary mice demonstrated a decline in fractional shortening over the time course of this study (~4 months to one year of age). The findings are consistent with a recent study of voluntary wheel and its beneficial effects on cardiomyopathic features of older mdx mice on the C57Bl/6 background, as both studies examined the effect of exercise on established disease 28 . We found the decline in LVEF was mitigated in a dose-dependent manner, with the moderate intensity cohort showing significantly delaying the decline of heart function.…”

Uniform sarcolemmal dystrophin expression is required to prevent extracellular microRNA release and improve dystrophic pathology

“…Female C57, non‐dystrophic Xist Δhs , and dystrophic mdx mice were harvested as controls in parallel (all n = 5). At 78 weeks of age, mice were sacrificed, and dystrophin protein expression was determined in the quadriceps femoris muscles by Western blot ( Figure B) . Each mdx‐Xist Δhs mouse was then retrospectively assigned to low (8.4–12.9%, n = 5), medium (18.8–21%, n = 5), or high (32.4–43.5%, n = 5) dystrophin‐expressing groups ( Figure A and B).…”

Accelerating the Mdx Heart Histo-Pathology through Physical Exercise

“…In this study, we aimed to accelerate and worsen the heart pathology in mdx mice, through exercise, avoiding additional genetic modifications. Unlike voluntary exercise, which has been found by some [ 17 , 18 , 19 ] but not all studies [ 20 , 21 ] to be beneficial, we reasoned that forced exercise might accelerate the mdx heart pathology. Indeed, “forced” running exercise on either a treadmill or by swimming is largely employed as a protocol to worsen the mdx phenotype and/or to evaluate the efficacy of therapeutic interventions with pharmacotherapies [ 22 , 23 , 24 , 25 , 26 , 27 ].…”