PGC1α expression is controlled in skeletal muscles by PPARβ, whose ablation results in fiber-type switching, obesity, and type 2 diabetes

Abstract

Mice in which peroxisome proliferator-activated receptor beta (PPARbeta) is selectively ablated in skeletal muscle myocytes were generated to elucidate the role played by PPARbeta signaling in these myocytes. These somatic mutant mice exhibited a muscle fiber-type switching toward lower oxidative capacity that preceded the development of obesity and diabetes, thus demonstrating that PPARbeta is instrumental in myocytes to the maintenance of oxidative fibers and that fiber-type switching is likely to be the cause and not the consequence of these metabolic disorders. We also show that PPARbeta stimulates in myocytes the expression of PGC1alpha, a coactivator of various transcription factors, known to play an important role in slow muscle fiber formation. Moreover, as the PGC1alpha promoter contains a PPAR response element, the effect of PPARbeta on the formation and/or maintenance of slow muscle fibers can be ascribed, at least in part, to a stimulation of PGC1alpha expression at the transcriptional level.

Neuregulins Increase Mitochondrial Oxidative Capacity and Insulin Sensitivity in Skeletal Muscle Cells

“…The latter is necessary for neuregulins to increase cellular mitochondrial content. The study confirms previous reports that indicate PPAR␦ is a key element in the regulation of oxidative metabolism in skeletal muscle (19,(37)(38)(39). However, our results do not rule out the need for other transcription factors in neuregulin action in mitochondrial gene expression such as GA-binding protein (GABP)-␣ and -␤ (their human heteromeric binding form also known as NRF-2), whose transcriptional activity is increased by neuregulins in muscle cells (40).…”

Excess Lipid Availability Increases Mitochondrial Fatty Acid Oxidative Capacity in Muscle

“…Fatty acids are known ligands for the PPAR family of nuclear hormone receptors, and part of the increase in fatty acid oxidative capacity in the current study may be related to direct activation of PPAR␣ or PPAR␦ by fatty acids. In skeletal muscle, activation of PPAR␦ has been shown to increase expression of PGC-1␣ (38). PGC-1␣ is also known to coactivate PPAR␦ (39), resulting in a feed-forward loop that stabilizes PGC-1␣ protein expression and drives the transcription of genes associated with fatty acid metabolism (38).…”

“…In skeletal muscle, activation of PPAR␦ has been shown to increase expression of PGC-1␣ (38). PGC-1␣ is also known to coactivate PPAR␦ (39), resulting in a feed-forward loop that stabilizes PGC-1␣ protein expression and drives the transcription of genes associated with fatty acid metabolism (38).…”

Fish protein intake induces fast-muscle hypertrophy and reduces liver lipids and serum glucose levels in rats

“…10,11) In the animal experiments, muscle fiber type has been shown to be related to diabetes and obesity. 12,13) Modification of muscle fiber types is also reported in other fields such as sports nutrition and anti-aging. Thus, it is meaningful to modulate muscle fiber type as desired with the use of food.…”