Age‐related muscle atrophy? Mitofusin 2 the rescue

Sarcopenia, or the progressive loss of muscle mass and function associated with aging, is a fundamental contributor to disability and loss of autonomy in the elderly, leading to frailty and a decrease in the quality of life.1 Several molecular alterations have been proposed to contribute to the development of sarcopenia, such as increased inflammation, altered proteostasis, a decrease in motor unit number, and altered satellite cell number or function. Among them, the increase of damaged mitochondria has emerged as one of the main contributors to age-related muscle alterations.2 In the last few years, it has been shown that mitochondrial dynamics and mitophagy (selective degradation of mitochondria by autophagy) are key processes in the maintenance of mitochondrial health,3, 4 and importantly, their deregulation has been found to contribute to the accumulation of damaged mitochondria in aged muscles.5 In this regard, it has previously been shown that ablation of the mitochondrial fusion protein Mitofusin 2 (MFN2) in skeletal muscle leads to muscle atrophy and sarcopenia by a deregulation of both mitochondrial dynamics and mitophagy.6 In this issue of Acta Physiologica, Cefis et al.7 explore the possibility of whether overexpression of MFN2 in muscle might be useful to counteract muscle atrophy and sarcopenia in wild-type (WT) mice. Although muscle re-expression of MFN2 has already been shown to prevent muscle atrophy in Mfn2KO mice,6 the evaluation of whether enhanced expression of MFN2 in WT old mice could improve muscle atrophy had not been addressed yet. In their study, Cefis et al. use adeno-associated viruses (AAV) to overexpress MFN2 in glycolytic (EDL) and glycolytic/oxidative (TA) skeletal muscles, using 7- and 20-month-old C57BL/6J mice. Each animal serves as its own control by receiving intramuscular injections of AAV containing the MFN2 construct (AAV-MFN2) in the right leg, while the left leg is injected with a control construct (AAV-GFP). After 4 months of AAV injection, MFN2 protein levels in muscles from old mice increase around 20%–25% compared to AAV-GFP-injected muscles, which is associated with an increase in muscle mass and cross-sectional area (CSA), suggesting a decline in age-associated muscle atrophy. Importantly, no signs of necrosis, inflammation, or fibrosis—calculated as a "healthy index" from tissue sections H&E stained—are observed. Interestingly, MFN2 overexpression in muscles from young mice also leads to increased muscle weight and CSA without signs of muscle damage, suggesting that the effects of MFN2 overexpression are not restricted to the context of aging. An interesting observation of this study is that the authors do not find a decrease in muscle MFN2 protein levels during aging, as previously described,6 which may be explained by differences in the muscles analyzed (oxidative versus glycolytic), pointing to a different age-related regulation of MFN2 in the different types of muscle fibres. Next, the authors examine the effect of MFN2 overexpression on mitochondrial performance. Surprisingly, measurements of mitochondrial respiration and H2O2 emission in permeabilized fibres bring up no differences between MFN2-overexpressing and control muscles. Nevertheless, mitochondrial mass, measured by the expression of a combination of several mitochondrial proteins, is reduced upon MFN2 overexpression. Therefore, these results suggest that MFN2 overexpression might improve mitochondrial quality, possibly by enhancing the degradation of damaged mitochondria, which agrees with the decrease in mitophagy found in MFN2-ablated muscles.6 Mitochondrial dysfunction in muscle has been found to be associated with aging in several studies, although some discrepancies exist in the bibliography about this issue, probably due to different experimental approaches, muscles, and species analyzed (rats, mice, and humans).8, 9 In this study, the authors do not find changes in mitochondrial function and ROS production in aged muscles, suggesting that age-related muscle atrophy can develop without changes in mitochondrial respiration. Looking for a possible mechanism by which MFN2 overexpression protects from age-related muscle atrophy, the authors examine well-known pathways involved in muscle mass regulation. They find a limited number of changes, which may be a consequence of the long-term post-injection of AAVs (4 months) when the experiments have been performed. They describe no changes in MCU/PGC1a4, mTOR, or ER-stress protein markers expression. When analyzing autophagy/mitophagy markers, they only find a decrease in age-induced p62 accumulation in MFN2-ovexpressing muscles. Although more studies analyzing autophagic flux are needed, these results suggest that MFN2 overexpression can enhance autophagy in old muscles. Overall, although with some limitations, the major novelty of the study of Cefis et al. is the finding that MFN2 expression can be safely induced in muscle, leading to an increase in muscle cross-sectional area. Therefore, the effects of MFN2 reported in this study pave the way for the possibility of targeting this protein to combat age-related muscle atrophy and other diseases associated with muscle wasting. Although further studies are needed to understand the molecular mechanisms involved and whether MFN2 induction can ameliorate the functional impairments of aged muscle, the authors describe interesting results and provide a proof of concept for enhanced MFN2 expression as a valuable option for the management and treatment of age-related muscle atrophy and sarcopenia. A.C. is a recipient of a post-doctoral fellowship from MSCA-Sello de Excelencia ISCIII-HEALTH, funded by NextGenerationEU/PRTR. This study is supported by research grant PID2021-124645OB-100 funded by MICIU/AEI/10.13039/501100011033 and FEDER, UE. The authors declare no conflict of interest.