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Aberrant calcium influx causes fiber type shift and mitochondrial loss in skeletal muscle

ABSTRACT: Skeletal muscle excitation-contraction (EC) coupling is independent of calcium influx. In fact alternative splicing of the voltage-gated calcium channel CaV1.1 actively suppresses calcium currents in mature muscle. Why this might be necessary is not known. However, splicing defects causing aberrant expression of the calcium-conducting embryonic CaV1.1e splice variant correlate with muscle weakness in myotonic dystrophy. Here we deleted CaV1.1 exon 29 in mice. The continued expression of CaV1.1e resulted in increased calcium influx during EC coupling and spontaneous calcium sparks. While overall motor performance was normal, muscle force was reduced, endurance enhanced, and the fiber type composition shifted toward slower fibers. In contrast, oxidative enzyme activity and the mitochondrial content declined. Together with the dysregulation of key regulators of the slow program these findings indicate that limiting calcium influx during skeletal muscle EC coupling is important for the calcium signal’s secondary function in the activity-dependent regulation of fiber type composition.

ORGANISM(S): Mus musculus

PROVIDER: GSE67803 | GEO | 2016/04/01

SECONDARY ACCESSION(S): PRJNA280959

REPOSITORIES: GEO

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Project description:This experiment was conducted to identify target genes of the microRNA-499 in skeletal muscle of transgenic mice that overexpressed miR-499. The following abstract from the submitted manuscript describes the major findings of this work. Coupling of mitochondrial function and skeletal muscle fiber type by a miR-499/Fnip1/AMPK circuit. Jing Liu, Xijun Liang, Danxia Zhou, Ling Lai, Tingting Fu, Yan Kong, Qian Zhou, Rick B. Vega, Min-Sheng Zhu, Daniel P. Kelly, Xiang Gao, and Zhenji Gan. 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 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-1a-dependent mitochondrial oxidative metabolism program to match shifts in slow-twitch muscle fiber composition. Mechanistically, miR-499 directly targets Fnip1, a known AMP-activated protein kinase (AMPK)-interacting protein that negatively regulates AMPK, a known activator of PGC-1a. Inhibition of Fnip1 reactivated AMPK/PGC-1a 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. Keywords: muscle, contractile fiber type, mitochondrial function, microRNA, gene regulation RNA from three wild-type (non-transgenic (NTG)) and three miR-499 overexpressing (MCK-miR-499) mice was analyzed. three replicates of each are provided.

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Aberrant calcium influx causes fiber type shift and mitochondrial loss in skeletal muscle

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