Oxidative Stress-Mediated Skeletal Muscle Degeneration: Molecules, Mechanisms, and Therapies

Abstract

Oxidative stress is a loss of balance between the production of reactive oxygen species during cellular metabolism and the mechanisms that clear these species to maintain cellular redox homeostasis. Increased oxidative stress has been associated with muscular dystrophy, and many studies have proposed mechanisms that bridge these two pathological conditions at the molecular level. In this review, the evidence indicating a causal role of oxidative stress in the pathogenesis of various muscular dystrophies is revisited. In particular, the mediation of cellular redox status in dystrophic muscle by NF-κB pathway, autophagy, telomere shortening, and epigenetic regulation are discussed. Lastly, the current stance of targeting these pathways using antioxidant therapies in preclinical and clinical trials is examined.

Figure 1

Multiple sites of ROS and RNS production are present in skeletal muscle cells. The network of different proteins that leads to ROS/RNS production in the extracellular, cytosolic, and mitochondrial compartments of skeletal muscle cell is illustrated. XO: xanthine oxidase; NOX: NADPH oxidase; DG: dystrophin-glycoprotein; nNOS: neuronal nitric oxide synthase; PLA2: phospholipase A2; I–V: complexes of electron transport/oxidative phosphorylation; UCP: uncoupling protein; O₂: oxygen; ^∙O₂ ⁻: superoxide; H₂O₂: hydrogen peroxide; ^∙NO: nitric oxide; ONOO⁻: peroxynitrite.

Figure 2

Mechanisms leading to oxidative stress in skeletal muscle. This schematic illustrates cellular mechanisms that are known to exert either prooxidant or antioxidant effects. Aberrant regulation of these pro- and antioxidative processes is indicated to play a role in muscle degenerative disorders. NFκB: nuclear factor kappa-light-chain-enhancer of activated B cells; Bmi1: B lymphoma Mo-MLV insertion region 1 homolog; PGC-1α: peroxisome proliferator-activated receptor gamma coactivator 1-alpha; FoxO: forkhead box O; mTOR: mechanistic or mammalian target of rapamycin; AMPK: adenosine monophosphate-activated protein kinase; PI3K: phosphoinositide 3-kinase; IGF: insulin-like growth factor.