Mitochondria are essential for maintaining skeletal muscle metabolic homeostasis during adaptive response to a myriad of physiologic or pathophysiological stresses. The mechanisms by which mitochondrial function and contractile fiber type are concordantly regulated to ensure muscle function remain poorly understood. Evidence is emerging that the Folliculin interacting protein 1 ( Fnip1 ) is involved in skeletal muscle fiber type specification, function, and disease. In this study, Fnip1 was specifically expressed in skeletal muscle in Fnip1 -transgenic ( Fnip1 ~(Tg)) mice. Fnip1 ~(Tg) mice were crossed with Fnip1- knockout ( Fnip1 ~(KO)) mice to generate Fnip1 ~(TgKO) mice expressing Fnip1 only in skeletal muscle but not in other tissues. Our results indicate that, in addition to the known role in type I fiber program, FNIP1 exerts control upon muscle mitochondrial oxidative program through AMPK signaling. Indeed, basal levels of FNIP1 are sufficient to inhibit AMPK but not mTORC1 activity in skeletal muscle cells. Gain-of-function and loss-of-function strategies in mice, together with assessment of primary muscle cells, demonstrated that skeletal muscle mitochondrial program is suppressed via the inhibitory actions of FNIP1 on AMPK. Surprisingly, the FNIP1 actions on type I fiber program is independent of AMPK and its downstream PGC-1α. These studies provide a vital framework for understanding the intrinsic role of FNIP1 as a crucial factor in the concerted regulation of mitochondrial function and muscle fiber type that determine muscle fitness. Author summary Mitochondria provide an essential source of energy to drive cellular processes and the function of mitochondria is particularly important in skeletal muscle, a metabolically demanding tissue that depends critically on mitochondria, accounting for ~40% of total body mass. In this study, we discovered an essential function of adaptor protein FNIP1 in the coordinated regulation of the mitochondrial and structural programs controlling muscle fitness. Using both gain-of-function and loss-of-function strategies in mice and muscle cells, we provide clear genetic data that demonstrate FNIP1-dependent signaling is crucial for muscle mitochondrial remodeling as well as type I muscle fiber specification. We also uncover that FNIP1 exerts control upon muscle mitochondrial program through AMPK but not mTORC1 signaling. Furthermore, we demonstrate that FNIP1 acts independently of PGC-1α to regulate fiber type specification. Hence, our study emphasizes FNIP1 as a dominant factor that coordinates mitochondrial and muscle fiber type programs that govern muscle fitness.
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