Mitochondrial dysfunction: roles in skeletal muscle atrophy

Abstract

Mitochondria play important roles in maintaining cellular homeostasis and skeletal muscle health, and damage to mitochondria can lead to a series of pathophysiological changes. Mitochondrial dysfunction can lead to skeletal muscle atrophy, and its molecular mechanism leading to skeletal muscle atrophy is complex. Understanding the pathogenesis of mitochondrial dysfunction is useful for the prevention and treatment of skeletal muscle atrophy, and finding drugs and methods to target and modulate mitochondrial function are urgent tasks in the prevention and treatment of skeletal muscle atrophy. In this review, we first discussed the roles of normal mitochondria in skeletal muscle. Importantly, we described the effect of mitochondrial dysfunction on skeletal muscle atrophy and the molecular mechanisms involved. Furthermore, the regulatory roles of different signaling pathways (AMPK-SIRT1-PGC-1α, IGF-1-PI3K-Akt-mTOR, FoxOs, JAK-STAT3, TGF-β-Smad2/3 and NF-κB pathways, etc.) and the roles of mitochondrial factors were investigated in mitochondrial dysfunction. Next, we analyzed the manifestations of mitochondrial dysfunction in muscle atrophy caused by different diseases. Finally, we summarized the preventive and therapeutic effects of targeted regulation of mitochondrial function on skeletal muscle atrophy, including drug therapy, exercise and diet, gene therapy, stem cell therapy and physical therapy. This review is of great significance for the holistic understanding of the important role of mitochondria in skeletal muscle, which is helpful for researchers to further understanding the molecular regulatory mechanism of skeletal muscle atrophy, and has an important inspiring role for the development of therapeutic strategies for muscle atrophy targeting mitochondria in the future.

Muscle‐specific overexpression of Atg2 gene and endurance exercise delay age‐related deteriorations of skeletal muscle and heart function via activating the AMPK/Sirt1/PGC‐1α pathway in male Drosophila

“…42,43 This evidence suggests an important role for the AMPK/Sirt1/PGC-1α signaling pathway in regulating mitochondrial biogenesis during exercise and that activation of this pathway reduces the negative effects of oxidative stress on skeletal muscle. 32 In the present study, we found that endurance exercise significantly delayed the age-related accelerated decline in climbing ability in Atg2 knockdown Drosophila. We also found that endurance exercise significantly increased AMPK/Sirt1/PGC-1α pathway activity significantly reduced muscle oxidative in Atg2 senescent Drosophila.…”

“…Cells lacking AMPK activity exhibit elevated mitochondrial ROS levels, increased oxidative damage, and premature senescence 42,43 . This evidence suggests an important role for the AMPK/Sirt1/PGC‐1α signaling pathway in regulating mitochondrial biogenesis during exercise and that activation of this pathway reduces the negative effects of oxidative stress on skeletal muscle 32 …”

“…In obesity‐induced muscle atrophy, fibroblast growth factor 19 promotes mitochondrial biogenesis and antioxidant responses via the AMPK/PGC‐1α pathway, thereby attenuating the effects of palmitate on mitochondrial dysfunction and oxidative stress 30 . Ampelopsin attenuates d‐galactose (d‐gal)‐induced skeletal muscle atrophy in aged rats through activation of the AMPK/SIRT1/PGC‐1α pathway 31,32 . Thus, these evidences suggest that either muscle Atg2 overexpression or knockdown can affect muscle structure and function (overexpression is beneficial, knockdown is detrimental) by mechanisms that may be related to promotion/inhibition of AMPK/SIRT1/PGC‐1α pathway activity and improvement/disruption of the balance of oxidative and antioxidant systems.…”

“…30 Ampelopsin attenuates d-galactose (d-gal)-induced skeletal muscle atrophy in aged rats through activation of the AMPK/SIRT1/PGC-1α pathway. 31,32 Thus, these evidences suggest that either muscle Atg2 overexpression or knockdown can affect muscle structure and function (overexpression is beneficial, knockdown is detrimental) by mechanisms that may be related to promotion/inhibition of AMPK/SIRT1/ PGC-1α pathway activity and improvement/disruption of the balance of oxidative and antioxidant systems. When engaged in prolonged aerobic and resistance exercise, aging skeletal muscle expresses more autophagy-associated proteins, which induce skeletal muscle autophagy and delay the loss of muscle mass.…”

Morroniside Protects C2C12 Myoblasts from Oxidative Damage Caused by ROS-Mediated Mitochondrial Damage and Induction of Endoplasmic Reticulum Stress

“…Additionally, ROS contribute to the initiation of apoptosis through endoplasmic reticulum (ER) stress ( Liu et al ., 2022 ; Wang et al ., 2023 ). In particular, oxidative stress caused by insufficient removal of ROS, which occurs when muscles consume large amounts of oxygen for contractile activity, directly or indirectly affects muscle cell function and damages DNA and intracellular organelles ( Foreman et al ., 2021 ; Chen et al ., 2023 ). For example, ROS inhibits muscle differentiation from myoblasts to myotubes, promotes muscle atrophy through catabolism of differentiated muscle cells, and acts as a pathological cause of various muscle disorders ( Abrigo et al ., 2019 ; Alizadeh Pahlavani et al ., 2022 ).…”