Program in Gene Function and Expression; Program in Molecular Medicine
Peroxisome Proliferator-Activated Receptors; Muscle, Skeletal
Cell and Developmental Biology | Life Sciences | Medicine and Health Sciences | Physiology
Peroxisome proliferator-activated receptors (PPARs) are a class of nuclear receptors that play important roles in development and energy metabolism. Whereas PPARdelta 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 Ppardelta leads to embryonic lethality, we sought to address this question by conditional knockout (cKO) of Ppardelta using Myf5-Cre/Ppardeltaflox/flox alleles to ablate PPARdelta in myogenic progenitor cells. Although Ppardelta-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. Ppardelta-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 Ppardelta-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 Ppardelta-cKO muscles under both quiescent and regenerating conditions, suggesting that PPARdelta acts through FoxO1 in regulating muscle progenitor cells. These results support a function of PPARdelta in regulating skeletal muscle metabolism and insulin sensitivity, and they establish a novel role of PPARdelta in muscle progenitor cells and postnatal muscle regeneration.