Role of PPARδ in satellite cells and muscle differentiation
Abstract
Peroxisome proliferator-activated receptors (PPARs) are a class of nuclear receptors that have been shown to play critical roles in development and metabolism. Whereas PPARδ has been shown to be a potent regulator of mitochondria biosynthesis and slow muscle fiber types, the potential function of PPARδ in skeletal muscle progenitor cells is still unknown. The current research aims to address this question using a combination of conditional gene mutation, gene expression, in vitro cell culture and in vivo muscle regeneration approaches. As constitutive mutation of PPARδ leads to embryonic lethality, we developed a mouse model carrying a Myf5-Cre allele together with a floxed PPARδ gene for Cre-LoxP mediated conditional mutation of the PPARδ gene in the Myf5-derived myogenic lineage, including 90% of myogenic progenitors (satellite cells). We found that conditional mutant mice had 40% fewer satellite cells compared to wild type littermates. In addition, satellite cells from the mutant mice exhibited reduced growth kinetics and reduced proliferation in vitro compared to those from wild type mice. Furthermore, mutant muscle regeneration after injury with cardiotoxin was delayed. Although conditional mutant mice were born normally and initially displayed no difference in body weight, muscle size or muscle composition, they later developed metabolic syndrome manifested by increased body weight (due to accumulation of fat mass) and reduced response to glucose challenge at 8–9 months old. Gene expression analysis showed reduced expression mCPT1β and Foxo1 after PPARδ conditional knockdown and thus, PPARδ may act through mCPT1β or Foxo1 to regulate myogenic cells. These results establish a previously unappreciated role of PPARδ in muscle progenitor cells and postnatal muscle regeneration, and further suggest a function of PPARδ in regulating skeletal muscle metabolism and insulin sensitivity.
Degree
M.S.
Advisors
Kuang, Purdue University.
Subject Area
Molecular biology|Cellular biology
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