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. 2022 Apr 17;13(3):1673–1685. doi: 10.1002/jcsm.13000

Figure 2.

Figure 2

Function of autophagy in different stages of myogenic differentiation. (i) During aging, the ability of MuSCs to clear damaged cellular materials (specially mitochondria) through basal autophagy declines, which will result in higher levels of ROS. ROS can inhibit the expression of downstream target genes (related to cell cycle) by activating p16INK4a, so as to cause quiescent MuSCs to lose reversible quiescence by switching to an irreversible pre‐senescence state. (ii) The AMPK/p27Kip1 pathway may regulate the balance between autophagy and apoptosis in MuSCs, thus maintaining them in a steady‐state resting state. In senescent MuSCs, the phosphorylation of AMPK and its downstream target P27Kip1 decreased, and the resulting stress of suppressed autophagy makes MuSCs more prone to apoptosis. (iii) Sex steroid hormones controlled by the HPG axis transcriptionally induce the expression of Tfeb in MuSCs. TFEB systemically controls autophagosome clearance in MuSCs and reduces the accumulation of ROS. Accordingly, the HPG‐TFEB‐autophagosome pathway maintains stemness and quiescence of MuSCs. (iv) SIRT1 activates autophagy by mediating ATG7 deacetylation and AMPK phosphorylation. The increased level of autophagy promotes ATP production and mitochondrial activity to meet biological energy demand for MuSCs during this key transition from quiescence to activation. (v) In the process of differentiation, myoblasts first clear the original mitochondria of glycolysis mode through mitophagy, and then regenerate mitochondria of new metabolic mode (oxidative phosphorylation) to meet the increased energy demand of myotubes. PINK1 and ULK1 may be involved in the regulation of mitophagy. (vi) Autophagy regulates mitochondria‐mediated apoptotic signalling during myoblast differentiation, and protects differentiating myoblasts from apoptotic cell death. ROS, reactive oxygen species; AMPK, AMP‐activated protein kinase; HPG, hypothalamic–pituitary‐gonad; TFEB, transcription of the transcription factor EB; SIRT1, Sirtuin1; ATP, adenosine triphosphate; ATG, autophagy related; PINK1, PTEN induced putative kinase 1; ULK1, Unc‐51‐like kinase 1.