A new therapeutic effect of simvastatin revealed by functional improvement in muscular dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is a lethal, degenerative muscle disease with no effective treatment. DMD muscle pathogenesis is characterized by chronic inflammation, oxidative stress, and fibrosis. Statins, cholesterol-lowering drugs, inhibit these deleterious processes in ischemic diseases affecting skeletal muscle, and therefore have potential to improve DMD. However, statins have not been considered for DMD, or other muscular dystrophies, principally because skeletal-muscle-related symptoms are rare, but widely publicized, side effects of these drugs. Here we show positive effects of statins in dystrophic skeletal muscle. Simvastatin dramatically reduced damage and enhanced muscle function in dystrophic (mdx) mice. Long-term simvastatin treatment vastly improved overall muscle health in mdx mice, reducing plasma creatine kinase activity, an established measure of muscle damage, to nearnormal levels. This reduction was accompanied by reduced inflammation, more oxidative muscle fibers, and improved strength of the weak diaphragm muscle. Shorter-term treatment protected against muscle fatigue and increased mdx hindlimb muscle force by 40%, a value comparable to current dystrophin gene-based therapies. Increased force correlated with reduced NADPH Oxidase 2 protein expression, the major source of oxidative stress in dystrophic muscle. Finally, in old mdx mice with severe muscle degeneration, simvastatin enhanced diaphragm force and halved fibrosis, a major cause of functional decline in DMD. These improvements were accompanied by autophagy activation, a recent therapeutic target for DMD, and less oxidative stress. Together, our findings highlight that simvastatin substantially improves the overall health and function of dystrophic skeletal muscles and may provide an unexpected, novel therapy for DMD and related neuromuscular diseases.statin | muscular dystrophy | fibrosis | inflammation | muscle force D uchenne muscular dystrophy (DMD) is a degenerative muscle disease caused by the absence of dystrophin, a large protein that links the cytoskeleton to the surface membrane in muscle cells. Loss of dystrophin causes widespread effects on muscle signaling and metabolic pathways, leading to cell death and progressive replacement of functional muscle fibers with fibrotic connective tissue. This process results in profound muscle weakness, usually leaving DMD boys wheelchair-bound by their early teenage years and leading to death from the consequences of respiratory and/or cardiac muscle failure by age 20-30. Current treatments, such as corticosteroids, slow disease progression only marginally (1), whereas gene-based approaches, such as exonskipping, although promising in preclinical studies, will need to overcome many technical and regulatory hurdles, as well becoming affordable, before they are a widely available therapy for DMD patients (2). Therefore, efficacious pharmaceutical agents that are cost-effective and already approved for human use are particularly attractive candidates for the current treatment of DM...

Autophagy regulates satellite cell ability to regenerate normal and dystrophic muscles

“…Other studies demonstrates that the E3 ubiquitin ligase TNF receptor-associated factor 6 (TRAF6), which regulates autophagy, displays a stage-dependent effect in mdx mice, 25 further supporting the notion that unbalanced autophagy occurs in DMD. Defective autophagy of mdx animals is restored by rapamycin delivery through nanoparticles 45 and Simvastin treatment that reduces ROS by enhancing the autophagic process 27,46 leading to improved physical performance.…”

“…[21][22][23] Recent investigations have begun to elucidate the role of autophagy in other muscular disorders, including DMD. [24][25][26][27] Moreover, it has been shown that autophagy is implicated in loss of muscle mass in the elderly, referred as sarcopenia, 28,29 as well as in myofiber survival. 30 Multiple lines of evidence indicate that autophagy diminishes with aging, 31 premature aging correlates with autophagy inhibition, 29 while increased autophagy (as by mean of calorie restriction) delays aging and extends longevity.…”

Disrupted autophagy undermines skeletal muscle adaptation and integrity

“…Although key details remain to be addressed, autophagy is co-substantial to skeletal muscle maintenance and adaptation and has already been targeted to ameliorate disease (Raben et al 2010; Carmignac et al 2011; Grumati et al 2010, 2011 Bhuiyan et al 2013; Cabet et al 2015; Chrisam et al 2015; Hidvegi et al 2015; Hsueh et al 2016; Whitehead et al 2015; Foltz et al 2016). A greater understanding of tension-induced autophagy systems may help to elucidate connections between protein unfolding and mTOR-dependent or mTOR-independent hypertrophic responses.…”

Altered short-term synaptic plasticity and reduced muscle strength in mice with impaired regulation of presynaptic Ca V 2.1 Ca 2+ channels

“…TA muscle function of WT and IM-AA mice (8-11 wk old) was measured in situ as described previously (31). In brief, mice were anesthetized with Avertin (625 mg/kg i.p.)…”