Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2024 Apr 23;29(1):59.
doi: 10.1186/s11658-024-00572-y.

The role of mitochondrial dynamics and mitophagy in skeletal muscle atrophy: from molecular mechanisms to therapeutic insights

Yuhang Lei #  1   2 , Mailin Gan #  1   2 , Yanhao Qiu  1   2 , Qiuyang Chen  1   2 , Xingyu Wang  1   2 , Tianci Liao  1   2 , Mengying Zhao  1   2 , Lei Chen  1   2 , Shunhua Zhang  1   2 , Ye Zhao  1   2 , Lili Niu  1   2 , Yan Wang  1   2 , Li Zhu  3   4 , Linyuan Shen  5   6
Affiliations
Review

The role of mitochondrial dynamics and mitophagy in skeletal muscle atrophy: from molecular mechanisms to therapeutic insights

Yuhang Lei et al. Cell Mol Biol Lett. .

Abstract

Skeletal muscle is the largest metabolic organ of the human body. Maintaining the best quality control and functional integrity of mitochondria is essential for the health of skeletal muscle. However, mitochondrial dysfunction characterized by mitochondrial dynamic imbalance and mitophagy disruption can lead to varying degrees of muscle atrophy, but the underlying mechanism of action is still unclear. Although mitochondrial dynamics and mitophagy are two different mitochondrial quality control mechanisms, a large amount of evidence has indicated that they are interrelated and mutually regulated. The former maintains the balance of the mitochondrial network, eliminates damaged or aged mitochondria, and enables cells to survive normally. The latter degrades damaged or aged mitochondria through the lysosomal pathway, ensuring cellular functional health and metabolic homeostasis. Skeletal muscle atrophy is considered an urgent global health issue. Understanding and gaining knowledge about muscle atrophy caused by mitochondrial dysfunction, particularly focusing on mitochondrial dynamics and mitochondrial autophagy, can greatly contribute to the prevention and treatment of muscle atrophy. In this review, we critically summarize the recent research progress on mitochondrial dynamics and mitophagy in skeletal muscle atrophy, and expound on the intrinsic molecular mechanism of skeletal muscle atrophy caused by mitochondrial dynamics and mitophagy. Importantly, we emphasize the potential of targeting mitochondrial dynamics and mitophagy as therapeutic strategies for the prevention and treatment of muscle atrophy, including pharmacological treatment and exercise therapy, and summarize effective methods for the treatment of skeletal muscle atrophy.

Keywords: Intermodulation; Mitochondrial dynamics; Mitophagy; Molecular mechanism; Prevention and treatment; Skeletal muscle atrophy.

PubMed Disclaimer

Conflict of interest statement

The authors declare no potential conflicts of interest.

Figures

Fig.1
Fig.1
The molecular mechanisms of skeletal muscle atrophy associated with mitochondrial dynamics and mitophagy. When individuals encounter diverse endogenous stressors, such as denervation, aging, chronic inflammation, and exogenous factors, such as hypoxia, starvation, or minimal exercise, the muscle cell mitochondrial membrane potential diminishes while reactive oxygen species accumulate. This scenario prompts the initiation of multiple signaling pathways and activation of various non-coding RNAs, fostering an imbalance in mitochondrial dynamics and disrupting mitophagy in muscle cells. This, in turn, accelerates the process of muscle atrophy and degradation
Fig. 2
Fig. 2
Mutual regulation of mitophagy and mitochondrial dynamics. Initially, PINK1, a pivotal protein in mitophagy, directly phosphorylates DRP1 and MFN2, facilitating the activation of both mitochondrial fission and fusion. Moreover, phosphorylated MFN2 functions as a receptor for Parkin, subsequently initiating mitophagy. Furthermore, any mitochondrial breakage or swelling arising from irregularities in mitochondrial fusion or fission prompts the activation of mitophagy, ensuring the sustenance of a healthy mitochondrial network
Fig. 3
Fig. 3
The importance of mitochondrial dynamics in maintaining skeletal muscle health. An imbalance in mitochondrial fission and fusion precipitates mitochondrial dysfunction, a primary cause of muscle atrophy and degeneration. Conversely, restoring mitochondrial dynamics through treatment in the physiological state of atrophic muscles can impede the advancement of muscle atrophy
Fig. 4
Fig. 4
The mechanism of mitophagy under normal and abnormal physiological conditions. Under normal conditions, PINK1-mediated mitochondrial targeting and degradation inhibit parkin recruitment, thus preventing mitophagy initiation. In contrast, within damaged muscle mitochondria, PINK1 accumulation on the outer membrane triggers parkin recruitment and activation, initiating mitophagy. This cascade involves PINK1 accumulation, dimerization, and phosphorylation, which are crucial for parkin recruitment. Upon recruitment, PINK1 phosphorylates parkin at Ser65, activating it and promoting subsequent ubiquitin release
Fig. 5
Fig. 5
Schematic representation of potential therapeutic targets for skeletal muscle atrophy: mitophagy. Pharmacological modulation and exercise therapy are proposed as interventions to prevent and delay skeletal muscle atrophy. These drugs aim to restore physiological mitophagy levels and reduce the accumulation of damaged mitochondria in the body
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Baskin KK, Winders BR, Olson EN. Muscle as a “mediator” of systemic metabolism. Cell Metab. 2015;21(2):237–248. doi: 10.1016/j.cmet.2014.12.021. - DOI - PMC - PubMed
    1. Baehr LM, Hughes DC, Waddell DS, Bodine SC. SnapShot: skeletal muscle atrophy. Cell. 2022;185(9):1618–1618.e1. doi: 10.1016/j.cell.2022.03.028. - DOI - PubMed
    1. Anker SD, Morley JE, von Haehling S. Welcome to the ICD-10 code for sarcopenia. J Cachexia Sarcopenia Muscle. 2016;7(5):512–514. doi: 10.1002/jcsm.12147. - DOI - PMC - PubMed
    1. Riuzzi F, Sorci G, Arcuri C, Giambanco I, Bellezza I, Minelli A, et al. Cellular and molecular mechanisms of sarcopenia: the S100B perspective. J Cachexia Sarcopenia Muscle. 2018;9(7):1255–1268. doi: 10.1002/jcsm.12363. - DOI - PMC - PubMed
    1. Yang X, Xue P, Liu Z, Li W, Li C, Chen Z. SESN2 prevents the slow-to-fast myofiber shift in denervated atrophy via AMPK/PGC-1α pathway. Cell Mol Biol Lett. 2022;27(1):66. doi: 10.1186/s11658-022-00367-z. - DOI - PMC - PubMed