Complex Coordination of Cell Plasticity by a PGC-1α-controlled Transcriptional Network in Skeletal Muscle

Abstract

Skeletal muscle cells exhibit an enormous plastic capacity in order to adapt to external stimuli. Even though our overall understanding of the molecular mechanisms that underlie phenotypic changes in skeletal muscle cells remains poor, several factors involved in the regulation and coordination of relevant transcriptional programs have been identified in recent years. For example, the peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) is a central regulatory nexus in the adaptation of muscle to endurance training. Intriguingly, PGC-1α integrates numerous signaling pathways and translates their activity into various transcriptional programs. This selectivity is in part controlled by differential expression of PGC-1α variants and post-translational modifications of the PGC-1α protein. PGC-1α-controlled activation of transcriptional networks subsequently enables a spatio-temporal specification and hence allows a complex coordination of changes in metabolic and contractile properties, protein synthesis and degradation rates and other features of trained muscle. In this review, we discuss recent advances in our understanding of PGC-1α-regulated skeletal muscle cell plasticity in health and disease.

Paracrine cross-talk between skeletal muscle and macrophages in exercise by PGC-1α-controlled BNP

“…5B). Collectively, these results suggest that PGC-1α regulates BNP gene expression in conjunction with AP-1 and ERRα, similarly to what has been described for vascular endothelial growth factor and other PGC-1α target genes8.…”

“…PGC-1α induces genes involved in mitochondrial biogenesis, oxidative phosphorylation, vascularization and the contractile apparatus to enable a higher endurance capacity by co-activating an array of nuclear receptors and other transcription factors in a poorly understood complex transcriptional network89. In addition to the effects on energy metabolism in response to exercise, PGC-1α also has an immunomodulatory role1.…”

Muscle PGC-1α modulates satellite cell number and proliferation by remodeling the stem cell niche

“…This divergence is one of the very few parameters for which the PGC-1α-overexpressing and bona fide oxidative fibers are clearly different. In regard to most other metabolic and contractile properties, skeletal muscles of mTG animals closely mimic the phenotype of oxidative muscles [29]. Thus, the mechanistic underpinnings that control the diametrically opposite outcome between PGC-1α-overexpressing fibers with low vis-à-vis oxidative and endurance-trained muscle with high SC count is unclear.…”

Cyclin D1, cancer progression, and opportunities in cancer treatment

“…Notwithstanding, the cyclin D1-CDK4 axis impacts specific aspects of metabolic regulation. Peroxisome-proliferator-activated receptor (PPAR)-γ coactivator-1α (PGC-1α) regulates mitochondrial biogenesis, and acts as a transcriptional regulator that controls the expression of antioxidant genes, energy fuel selection, muscle fiber differentiation and transformation [103]. A recent study revealed that cyclin D1-CDK4 can modulate PGC-1α acetylation, putatively through GCN5 phosphorylation; moreover, the cyclin D1 T286A mutant can constitutively acetylate PGC-1α [104].…”