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.

Redox homeostasis and age‐related deficits in neuromuscular integrity and function

“…7,292 Potential therapies to combat the age-related deficits in skeletal muscle function There is significant academic and commercial interest in the development of therapies, of both pharmacological and nonpharmacological origin, to combat the loss of skeletal muscle mass and function, in the context of neuromuscular ageing and a wide range of myopathies. 293 Physical activity is one of the most effective interventions known to delay the progression of several aspects of muscle ageing. Similar to rodent models, 41,294 human studies have shown that physical activity is beneficial in promoting survival of motor units, 11 facilitating reinnervation of muscle fibres that become denervated secondary to impaired NMJ stability, 12 in attenuating age-related genotoxic stress 14 and preserving redox regulated adaptive responses.…”

“…300 The use of antioxidant therapies in muscular dystrophy has been described in a recent review. 293 Calorie or dietary restriction has shown to promote survival in mammals and delay the onset of numerous age-related phenotypes including sarcopenia. 301,302 At a biochemical level, calorie restriction interventions have shown to increase sirtuin 1 (a member of the sirtuin family linked to lifespan extension and enhanced mitochondrial biogenesis), the expression of peroxisome proliferator-activated receptor α (PGC1α) (a master regulator of mitochondrial biogenesis and RONS defence system), thus reducing oxidative damage and preserving mitochondrial structural and functional integrity in metabolically active tissues of rodents and humans.…”

Antioxidants Reduce Muscular Dystrophy in the dy2J/dy2J Mouse Model of Laminin α2 Chain-Deficient Muscular Dystrophy

“…Given the potentially important effect of ROS on muscle damage in dystrophic muscles, antioxidant treatment to reduce the oxidative stress has been postulated as a promising approach to improve muscle health [13,14]. N-acetylcysteine (NAC) is a compound with strong antioxidant properties.…”

Skeletal muscle and liver gene expression profiles in finishing steers supplemented with Amaize

“…In addition to its role in promoting intramuscular fat formation and backfat thickness, Amaize may also enhance the cellular stress response within skeletal muscle as a “collateral” effect of fat deposition by promoting the production of antioxidant factors within myocytes. Based on the bioinformatics analysis, examples of this effect include the upregulation of NR4A3 , PPARGC1A , ABRA , SESN2 , and TRIM63 genes in the skeletal muscles of Amaize steers; all of these genes encode powerful antioxidant factors that would protect the cells against oxidative stress damage through alleviating the over‐production of reactive oxygen species generated naturally during cellular metabolism (Choi, Ow, Yang, & Taneja, ; Mattox et al., ; Petrie, Suneja, Faidley, & Shields, ; Shin, Jin, Cho, & Ki, ). This further suggests a better anti‐oxidative protection in cattle fed Amaize, helping cells reach cellular redox homeostasis and inducing long‐term oxidative muscle adaptations in beef cattle.…”