Fnip1 Regulates Skeletal Muscle Fiber Type Specification, Fatigue Resistance, and Susceptibility to Muscular Dystrophy

Abstract

Skeletal muscle is characterized by the presence of two distinct categories of muscle fibers called Type I "red" slow twitch and Type II "white" fast twitch, which display marked differences in contraction strength, metabolic strategies, and susceptibility to fatigue. The relative representation of each fiber type can have major influences on the susceptibility to metabolic diseases including obesity, diabetes, and muscular dystrophies. However, the molecular factors controlling fiber type specification remain poorly defined. The objective of my thesis was to investigate the roles of a new metabolic protein called Folliculin Interacting Protein-1 (Fnip1) in fiber type specification and susceptibility to metabolic disease. Utilizing Fnip1 null mice we previously generated, we found that loss of Fnip1 dramatically increased the representation of Type I slow twitch fibers characterized by increased Myoglobin, MyH7, Succinate Dehydrogenase (SDH) , Troponin I1, Troponin C1, Troponin T1, and massive increases in mitochondria. Cultured <italic>Fnip1<italic> null muscle fibers had higher oxidative capacity, and isolated <italic>Fnip1<italic> null skeletal muscles sustained more prolonged contraction and had more rapid post-contraction recovery when compared to wild-type skeletal muscle. Biochemical and molecular analyses revealed increased activation of the metabolic sensor AMP kinase and increased expression of the master metabolic transcriptional regulator PGC1&alpha. Genetic disruption of PGC1&alpha rescued normal levels of Type I fibers markers in Fnip1-null mice. Remarkably, loss of Fnip1 nearly completely prevented muscle damage in a murine model of Duchenne muscular dystrophy. These results indicate that <italic>Fnip1<italic> controls skeletal muscle fiber type specification, and suggest that inhibition of <italic>Fnip1<italic> could be used as a potential therapeutic strategy to increase mitochondrial biogenesis and muscle function in patients with muscular dystrophy diseases, which are typified by defective mitochondrial function.