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, we demonstrate that FUNDC1, a mediator of mitophagy, plays a critical role in controlling muscle mitochondrial quality as well as metabolic homeostasis. Skeletal-muscle-specific ablation of FUNDC1 in mice resulted in LC3-mediated mitophagy defect, leading to impaired mitochondrial energetics. This caused decreased muscle fat utilization and endurance capacity during exercise. Interestingly, mice lacking muscle FUNDC1 were protected against high-fat-diet-induced obesity with improved systemic insulin sensitivity and glucose tolerance despite reduced muscle mitochondrial energetics. Mechanistically, FUNDC1 deficiency elicited a retrograde response in muscle that upregulated FGF21 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 dialog to regulate systemic metabolism.
Upon adaption of skeletal muscle to physiological and pathophysiological stimuli, muscle fiber type and mitochondrial function are coordinately regulated. Recent studies have identified pathways involved in control of contractile proteins of oxidative‐type fibers. However, the mechanism for coupling of mitochondrial function to the muscle contractile machinery during fiber type transition remains unknown. Here, we show that the expression of the genes encoding type I myosins, Myh7/Myh7b and their intronic miR‐208b/miR‐499, parallels mitochondrial function during fiber type transitions. Using in vivo approaches in mice, we found that miR‐499 drives a PGC‐1α‐dependent mitochondrial oxidative metabolism program to match shifts in slow‐twitch muscle fiber composition. Mechanistically, miR‐499 directly targets Fnip1, an AMP‐activated protein kinase (AMPK)‐interacting protein that negatively regulates AMPK, a known activator of PGC‐1α. Inhibition of Fnip1 reactivated AMPK/PGC‐1α signaling and mitochondrial function in myocytes. Restoration of the expression of miR‐499 in the mdx mouse model of Duchenne muscular dystrophy (DMD) reduced the severity of DMD. Thus, we have identified a miR‐499/Fnip1/AMPK circuit that can serve as a mechanism to couple muscle fiber type and mitochondrial function.
Edited by Jeffrey PessinLactate dehydrogenase (LDH) catalyzes the interconversion of pyruvate and lactate, which are critical fuel metabolites of skeletal muscle particularly during exercise. However, the physiological relevance of LDH remains poorly understood. Here we show that Ldhb expression is induced by exercise in human muscle and negatively correlated with changes in intramuscular pH levels, a marker of lactate production, during isometric exercise. We found that the expression of Ldhb is regulated by exerciseinduced peroxisome proliferator-activated receptor ␥ coactivator 1␣ (PGC-1␣). Ldhb gene promoter reporter studies demonstrated that PGC-1␣ activates Ldhb gene expression through multiple conserved estrogen-related receptor (ERR) and myocyte enhancer factor 2 (MEF2) binding sites. Transgenic mice overexpressing Ldhb in muscle (muscle creatine kinase (MCK)-Ldhb) exhibited increased exercise performance and enhanced oxygen consumption during exercise. MCK-Ldhb muscle was shown to have enhanced mitochondrial enzyme activity and increased mitochondrial gene expression, suggesting an adaptive oxidative muscle transformation. In addition, mitochondrial respiration capacity was increased and lactate production decreased in MCK-Ldhb skeletal myotubes in culture. Together, these results identified a previously unrecognized Ldhb-driven alteration in muscle mitochondrial function and suggested a mechanism for the adaptive metabolic response induced by exercise training.Muscle fitness and resistance to fatigue depend strongly on the capacity to burn the fuels, including fatty acids and glucose, to meet ATP demands (1-5). Exercise training is effective in improving muscle fitness by promoting favorable muscle metabolic reprograming including capacity for fuel burning, mitochondrial ATP production, and contraction (6 -13). Conversely, many chronic diseases, including obesity, diabetes, muscular diseases, and aging, are associated with decreased muscle fitness, contributing to a vicious cycle of inactivity and further promoting the progression of chronic diseases (6 -8, 11, 12, 14). Thus, a better understanding of the molecular regulatory pathways involved in the beneficial effects of exercise training on muscle fuel metabolism could yield novel therapeutic targets aimed at the prevention or treatment of diseases associated with muscle bioenergetics defects.The molecular and cellular mechanisms of skeletal muscle adaptation to exercise training are unclear. Exercise traininginduced adaptations in skeletal muscle are reflected, in part, by changes in transcriptional response and metabolite flux (1,2,4,5,11,15,16). Previous studies have demonstrated that the PGC-1␣ 3 transcriptional regulatory circuit, including the nuclear receptors PPAR and ERR, is a key transducer of exercise-responsive gene expression. The PGC-1␣ circuit regulates a broad array of genes involved in mitochondrial biogenesis and fuel metabolism (17)(18)(19)(20)(21)(22)(23)(24)(25). Evidence is also emerging that manipulation of metabolic enzyme or...
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