Abstract
Skeletal muscle fitness plays vital roles in human health and disease and is determined by developmental as well as physiological inputs. These inputs control and coordinate muscle fiber programs, including capacity for fuel burning, mitochondrial ATP production, and contraction. Recent studies have demonstrated crucial roles for nuclear receptors and their co-activators, and microRNAs (miRNAs) in the regulation of skeletal muscle energy metabolism and fiber type determination. In this review, we present recent progress in the study of nuclear receptor signaling and miRNA networks in muscle fiber type switching. We also discuss the therapeutic potential of nuclear receptors and miRNAs in disease states that are associated with loss of muscle fitness.
Highlights
Skeletal muscle is the biggest organ in the human body; it comprises ~40% of total body mass [1,2]
We present recent progress in the study of nuclear receptor signaling and miRNA networks in muscle fiber type switching
We discuss the therapeutic potential of nuclear receptors and miRNAs in disease states that are associated with loss of muscle fitness
Summary
Nuclear receptors are a class of transcription factor that can sense hormones ( termed ligands) and that regulate gene expression in response to external stimuli [10 13]. Transgenic mice, in which PPAR is overexpressed in skeletal muscle (MCK-PPARα mice), have up-regulated expression of genes involved in fatty acid uptake, oxidation, storage, and mitochondrial oxidative phosphorylation, and the mice have high fatty acid oxidation (FAO) rates and are resistant to high-fat-diet induced obesity [18]. On a high-fat-diet, the mice gain more weight and are more prone than controls to developing insulin resistance and glucose intolerance [26] Taken together, these data demonstrate that PPAR is necessary for both muscle FAO and the Type I fiber program, and that activation of PPAR in skeletal muscle can coordinately regulate muscle energy metabolism and fiber type switching to improve muscle fitness
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