PPARδ regulates satellite cell proliferation and skeletal muscle regeneration

Peroxisome proliferator-activated receptors (PPARs) are a class of nuclear receptors that play important roles in development and energy metabolism. Whereas PPAR delta has been shown to regulate mitochondrial biosynthesis and slow-muscle fiber types, its function in skeletal muscle progenitors (satellite cells) is unknown. Since constitutive mutation of Ppar delta leads to embryonic lethality, we sought to address this question by conditional knockout (cKO) of Ppar delta using Myf5-Cre/Ppar delta(flox/flox) alleles to ablate PPAR delta in myogenic progenitor cells. Although Ppar delta-cKO mice were born normally and initially displayed no difference in body weight, muscle size or muscle composition, they later developed metabolic syndrome, which manifested as increased body weight and reduced response to glucose challenge at age nine months. Ppar delta-cKO mice had 40% fewer satellite cells than their wild-type littermates, and these satellite cells exhibited reduced growth kinetics and proliferation in vitro. Furthermore, regeneration of Ppar delta-cKO muscles was impaired after cardiotoxin-induced injury. Gene expression analysis showed reduced expression of the Forkhead box class O transcription factor 1 (FoxO1) gene in Ppar delta-cKO muscles under both quiescent and regenerating conditions, suggesting that PPAR delta acts through FoxO1 in regulating muscle progenitor cells. These results support a function of PPAR delta in regulating skeletal muscle metabolism and insulin sensitivity, and they establish a novel role of PPAR delta in muscle progenitor cells and postnatal muscle regeneration.