Mitochondrial Dysfunction Is a Common Denominator Linking Skeletal Muscle Wasting Due to Disease, Aging, and Prolonged Inactivity

Abstract

Skeletal muscle is the most abundant tissue in the body and is required for numerous vital functions, including breathing and locomotion. Notably, deterioration of skeletal muscle mass is also highly correlated to mortality in patients suffering from chronic diseases (e.g., cancer). Numerous conditions can promote skeletal muscle wasting, including several chronic diseases, cancer chemotherapy, aging, and prolonged inactivity. Although the mechanisms responsible for this loss of muscle mass is multifactorial, mitochondrial dysfunction is predicted to be a major contributor to muscle wasting in various conditions. This systematic review will highlight the biochemical pathways that have been shown to link mitochondrial dysfunction to skeletal muscle wasting. Importantly, we will discuss the experimental evidence that connects mitochondrial dysfunction to muscle wasting in specific diseases (i.e., cancer and sepsis), aging, cancer chemotherapy, and prolonged muscle inactivity (e.g., limb immobilization). Finally, in hopes of stimulating future research, we conclude with a discussion of important future directions for research in the field of muscle wasting.

Chemotherapy-Induced Myopathy: The Dark Side of the Cachexia Sphere

“…These data suggest that stress-sensitive molecular targets could be common signalling pathways in chemotherapy-induced cachectic myopathy. Furthermore, excessive ROS production is associated with the onset of mitochondrial dysfunction, an event postulated to be the crucial trigger for the induction of skeletal muscle wasting by chemotherapy [ 36 ].…”

“…An emerging therapeutic class of particular interest to our laboratory group, and others, is the utility of mitoprotective compounds to combat skeletal muscle oxidative stress. Enhanced ROS production is a common underlying mechanism associated with multiple chemotherapies [ 32 , 33 ] and is a key contributing factor to mitochondrial dysfunction, a tenet of cachectic myopathy [ 36 , 37 ]. To date, mitoprotective compounds have not been evaluated in clinical trials.…”

Age-Related Alterations at Neuromuscular Junction: Role of Oxidative Stress and Epigenetic Modifications

“…In physiological conditions, a small number of electrons, passing through the chain, prematurely and incompletely reduces oxygen, producing the superoxide radicals; these are promptly scavenged by the cellular antioxidant enzymes, such as superoxide dismutase 1 (SOD1), to avoid oxidative damage of cellular macromolecules. Therefore, mitochondrial dysfunction and oxidative phosphorylation impairment determine the increase of ROS production and oxidative damage; these events, in turn, induce muscle cells to respond to the unbalanced redox homeostasis, upregulating the antioxidant enzymes [ 79 ]. Experimental evidence indicates that ROS may also act as chemical messengers, involved in receptor-mediated signaling pathways and transcriptional activation [ 80 ], suggesting that the cellular balance between ROS production and ROS scavenging is crucial to preserve cellular functionality [ 81 ].…”

Editorial: Autophagy and Mitophagy in Skeletal Muscle Health and Disease

“…Mitophagy is the selective autophagy of mitochondria and is essential to the clearance of defective mitochondria since impaired mitochondrial function and integrity is a major factor in the development of muscle fiber atrophy in several pathologies, including sarcopenia (age-related loss of muscle mass), cancer cachexia, severe sepsis-associated muscle dysfunction (Drake and Yan, 2017 ; Leduc-Gaudet et al, 2020 ; Hyatt and Powers, 2021 ). In non-muscle cells, the PTEN-induced kinase 1 (PINK1)-Parkin pathway has been recognized as a major regulator of mitophagy.…”