Mechanism of Gene Regulation in Skeletal Muscle Function

(JSNFS Award for Excellence in Research (2022))

Abstract

Skeletal muscle is the largest organ in the human body, playing important roles in exercise, energy expenditure and glucose/amino acid metabolism. Appropriate exercise coupled with sufficient nutrition increases muscle mass. In contrast, bedrest, aging, cancer, and other diseases lead to muscle atrophy, thus decreasing energy expenditure (leading to obesity) and glucose uptake, increasing the blood glucose level (resulting in diabetes) and reducing the quality of life. We have been investigating the role of a transcription factor, FOXO1, in regulation of skeletal muscle metabolism. In particular, since FOXO1 gene expression is induced by energy deprivation, we have produced transgenic mice overexpressing FOXO1 and found that they exhibit muscle atrophy. In addition to FOXO1, transcriptional coactivators, PGC1s, also play an important role in muscle metabolism. PGC1α expression increases in skeletal muscle upon exercise, leading to an increase of mitochondria in skeletal muscle and formation of red/slow fibers. Thus, we have been investigating in detail the mechanisms of muscle metabolism in vivo and in vitro, focusing on FOXO1 and PGC1α/PGC1β as major regulators. We hope to clarify the mechanisms that operate to prevent atrophy and dysfunction of skeletal muscle, coupled with a better understanding of the utility of functional foods for prevention and/or alleviation of these conditions.