PGC-1α-Mediated Branched-Chain Amino Acid Metabolism in the Skeletal Muscle

Abstract

Peroxisome proliferator-activated receptor (PPAR) γ coactivator 1α (PGC-1α) is a coactivator of various nuclear receptors and other transcription factors, which is involved in the regulation of energy metabolism, thermogenesis, and other biological processes that control phenotypic characteristics of various organ systems including skeletal muscle. PGC-1α in skeletal muscle is considered to be involved in contractile protein function, mitochondrial function, metabolic regulation, intracellular signaling, and transcriptional responses. Branched-chain amino acid (BCAA) metabolism mainly occurs in skeletal muscle mitochondria, and enzymes related to BCAA metabolism are increased by exercise. Using murine skeletal muscle overexpressing PGC-1α and cultured cells, we investigated whether PGC-1α stimulates BCAA metabolism by increasing the expression of enzymes involved in BCAA metabolism. Transgenic mice overexpressing PGC-1α specifically in the skeletal muscle had increased the expression of branched-chain aminotransferase (BCAT) 2, branched-chain α-keto acid dehydrogenase (BCKDH), which catabolize BCAA. The expression of BCKDH kinase (BCKDK), which phosphorylates BCKDH and suppresses its enzymatic activity, was unchanged. The amount of BCAA in the skeletal muscle was significantly decreased in the transgenic mice compared with that in the wild-type mice. The amount of glutamic acid, a metabolite of BCAA catabolism, was increased in the transgenic mice, suggesting the activation of muscle BCAA metabolism by PGC-1α. In C2C12 cells, the overexpression of PGC-1α significantly increased the expression of BCAT2 and BCKDH but not BCKDK. Thus, PGC-1α in the skeletal muscle is considered to significantly contribute to BCAA metabolism.

A single transcription factor is sufficient to induce and maintain secretory cell architecture

“…This cohort comprises genes involved in mitochondrial trafficking (Rab26, Ostm1, and Pon3) and those involved in amino acid metabolism (Aass, Bckdk, Gcdh, Qtrt1, and Wdyhv1) (Hutson 2006;Cleveland et al 2008;Wang et al 2009;Biela et al 2013;Seminotti et al 2013;Hatazawa et al 2014). The three trafficking genes seem to be involved in interactions between mitochondria and lysosomes as mentioned (Rab26 and Ostm1) and between mitochondria and the ER (Pon3).…”

FOXO1 activates glutamine synthetase gene in mouse skeletal muscles through a region downstream of 3′-UTR: possible contribution to ammonia detoxification

“…Western blot analysis. Western blot analysis was performed as described previously (13). Densitometric analysis was done using ImageJ software (http://rsb.info.nih.gov/ij/index.html).…”

Leucine stimulates PPARβ/δ-dependent mitochondrial biogenesis and oxidative metabolism with enhanced GLUT4 content and glucose uptake in myotubes

“…Leucine stimulates skeletal muscle PPARβ/δ 11 reduced cellular ATP content), however leucine appears to also function through additional mechanisms (such as heightened expression of leucine degradation enzymes [31,32] and/or through the activation of the eNOS/NO/cGMP/SIRT pathway leading to increased mitochondrial content) [31]. The expression of leucine degradation enzymes are regulated by PPARα and PGC-1α, and it has been suggested that increased mitochondrial content/enzyme content is necessary to support BCAA clearance [31,32].…”