The imprinted gene Pw1/Peg3 regulates skeletal muscle growth, satellite cell metabolic state, and self-renewal

• Main Authors: Rosa Maria Correra, David Ollitrault, Mariana Valente, Alessia Mazzola, Bjorn T. Adalsteinsson, Anne C. Ferguson-Smith, Giovanna Marazzi, David A. Sassoon
• Format: Article
• Language: English
• Published: Nature Publishing Group 2018-10-01
• Series: Scientific Reports
• Subjects: Satellite Cells; Myofiber Number; Skeletal Muscle Fiber Number; Maternal Allele; Mutant Muscle
• Online Access: https://doi.org/10.1038/s41598-018-32941-x

Abstract Pw1/Peg3 is an imprinted gene expressed from the paternally inherited allele. Several imprinted genes, including Pw1/Peg3, have been shown to regulate overall body size and play a role in adult stem cells. Pw1/Peg3 is expressed in muscle stem cells (satellite cells) as well as a progenitor subset of muscle interstitial cells (PICs) in adult skeletal muscle. We therefore examined the impact of loss-of-function of Pw1/Peg3 during skeletal muscle growth and in muscle stem cell behavior. We found that constitutive loss of Pw1/Peg3 function leads to a reduced muscle mass and myofiber number. In newborn mice, the reduction in fiber number is increased in homozygous mutants as compared to the deletion of only the paternal Pw1/Peg3 allele, indicating that the maternal allele is developmentally functional. Constitutive and a satellite cell-specific deletion of Pw1/Peg3, revealed impaired muscle regeneration and a reduced capacity of satellite cells for self-renewal. RNA sequencing analyses revealed a deregulation of genes that control mitochondrial function. Consistent with these observations, Pw1/Peg3 mutant satellite cells displayed increased mitochondrial activity coupled with accelerated proliferation and differentiation. Our data show that Pw1/Peg3 regulates muscle fiber number determination during fetal development in a gene-dosage manner and regulates satellite cell metabolism in the adult.