Role of PGC‐1α signaling in skeletal muscle health and disease

Abstract

This paper reviews the current understanding of the molecular basis of the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α)–mediated pathway and discusses the role of PGC-1α in skeletal muscle atrophy caused by immobilization. PGC-1α is the master transcription regulator that stimulates mitochondrial biogenesis, by upregulating nuclear respiratory factors (NRF-1, 2) and mitochondrial transcription factor A (Tfam), which leads to increased mitochondrial DNA replication and gene transcription. PGC-1α also regulates cellular oxidant–antioxidant homeostasis by stimulating the gene expression of superoxide dismutase-2 (SOD2), catalase, glutathione peroxidase 1 (GPx1), and uncoupling protein (UCP). Recent reports from muscle-specific PGC-1α overexpression underline the importance of PGC-1α in atrophied skeletal muscle, demonstrate enhancement of the PGC-1α mitochondrial biogenic pathway, and reduced oxidative damage. Thus, PGC-1α appears to play a protective role against atrophy-linked skeletal muscle deterioration.

The AMPK-PPARGC1A pathway is required for antimicrobial host defense through activation of autophagy

“…24,25 In studies of host metabolism, a protective role for the PPARGC1 family of transcriptional coactivators in the cellular stress response has been observed. 25 PPARGC1B is required for host defense against Listeria infection. 43 However, the roles of other PPARGC1 family genes in host defense are not well understood.…”

“…41,42 The finding that AICAR-induced PPARGC1A is required for the gene expression of Nfe2l-1, -2, and Tfam, in Mtb-infected macrophages is consistent with a previous similar observation for PPARGC1A in mitochondria-rich tissues (skeletal muscle, heart, liver, and brain). 24,25 In these tissues, PPARGC1A increases mitochondrial DNA replication and respiratory subunit mRNA transcription by upregulating mitochondrial biogenesis through induction of NRF-1, -2, and mitochondrial Tfam. 24,25 In studies of host metabolism, a protective role for the PPARGC1 family of transcriptional coactivators in the cellular stress response has been observed.…”

“…24,25 In these tissues, PPARGC1A increases mitochondrial DNA replication and respiratory subunit mRNA transcription by upregulating mitochondrial biogenesis through induction of NRF-1, -2, and mitochondrial Tfam. 24,25 In studies of host metabolism, a protective role for the PPARGC1 family of transcriptional coactivators in the cellular stress response has been observed. 25 PPARGC1B is required for host defense against Listeria infection.…”

“…24,25 However, little is known about the profiles of PPARGC1A and other genes involved in mitochondrial biogenesis in macrophages. We next investigated whether AICAR treatment of BMDMs leads to the induction of PPARGC1A and genes regulating mitochondrial biogenesis.…”

PGC-1α is associated with C2C12 Myoblast differentiation

“…PGC-1α interacts with nuclear receptors and transcription factors to activate transcription of specific target genes upon response to multiple stimuli including calcium ion, reactive oxygen species (ROS), insulin, thyroid hormone, estrogen, hypoxia, exercise, and cytokines et al [10]. As a prime regulator of mitochondrial content and oxidative metabolism, PGC-1α is critical in the maintenance of glucose, lipid, and energy homeostasis in muscle and other tissues [11][12][13][14].…”