The quality of mitochondria in skeletal muscle is essential for maintaining metabolic homeostasis during adaptive stress responses. However, the precise control mechanism of muscle mitochondrial quality and its physiological impacts remain unclear. Here, using two independent skeletal muscle-specific knockout mouse lines, we demonstrate that FUNDC1, a mediator of mitophagy, plays an essential role in controlling muscle mitochondrial quality as well as metabolic homeostasis. Mice with FUNDC1 deficiency in skeletal muscle (FUNDC1 mKO) showed decreased muscle fat utilization and endurance capacity (∼40%) compared to WT littermates during exercise. Analysis of biochemical markers of mitophagy revealed a marked decrease in mitochondrial localization of LC3-II and P62 protein levels, and this caused impaired mitochondrial respiration capacity. FUNDC1 loss-of-function studies in primary skeletal myocyte recapitulated defective mitophagy and impaired mitochondrial energetic as observed in FUNDC1 mKO muscle. Surprisingly, mice lacking muscle FUNDC1 were resistant to high fat diet (HFD) induced obesity despite reduced muscle mitochondrial energetics. Moreover, glucose and insulin tolerance tests demonstrated that HFD-fed FUNDC1 mKO mice were more tolerant to glucose challenge and more sensitive to insulin stimulation compared to HFD-fed WT controls. This seemingly paradoxical phenotype was due to enhanced fat burning in in adipose tissue. HFD-fed FUNDC1 mKO mice had markedly elevated expression of key thermogenic genes such as Ucp1 (17-fold), Cidea (13-fold), and Dio2 (9-fold) in white adipose. Mechanistically, FUNDC1 deficiency elicited a retrograde response in muscle that upregulated FGF-21 expression, thereby promoting the thermogenic remodeling of adipose tissue. Thus, these findings reveal a pivotal role of FUNDC1-dependent mitochondrial quality-control in mediating the muscle-adipose dialogue to regulate systemic metabolism.


T. Fu: None. Z. Xu: None. L. Liu: None. X. Liang: None. D. Zhou: None. Q. Guo: None. L. Xiao: None. Z. Gan: None.

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