Premature aging in skeletal muscle lacking serum response factor.
Aging is associated with a progressive loss of muscle mass, increased adiposity and fibrosis that leads to sarcopenia. At the molecular level, muscle aging is known to alter the expression of a variety of genes but very little is known about the molecular effectors involved. SRF (Serum Response Factor) is a crucial transcription factor for muscle-specific gene expression and for post-natal skeletal muscle growth. To assess its role in adult skeletal muscle physiology, we developed a post-mitotic myofiber-specific and tamoxifen-inducible SRF knockout model. Five months after SRF loss, no obvious muscle phenotype was observed suggesting that SRF is not crucial for myofiber maintenance. However, mutant mice progressively developed IIB myofiber-specific atrophy accompanied by a metabolic switch towards a more oxidative phenotype, muscular lipid accumulation, sarcomere disorganization and fibrosis. After injury, mutant muscles exhibited an altered regeneration process, showing smaller regenerated fibers and persistent fibrosis. All of these features are strongly reminiscent of abnormalities encountered in aging skeletal muscle. Interestingly, we also observed an important age associated decrease in SRF expression in mice and human muscles. Altogether, these results suggest that a naturally occurring SRF down-regulation precedes and contributes to the muscle aging process. Indeed, triggering SRF loss in the muscles of mutant mice results in an accelerated aging process.
Lahoute
Charlotte
C
Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France.
Sotiropoulos
Athanassia
A
Favier
Marilyne
M
Guillet-Deniau
Isabelle
I
Charvet
Claude
C
Ferry
Arnaud
A
Butler-Browne
Gillian
G
Metzger
Daniel
D
Tuil
David
D
Daegelen
Dominique
D
D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D019588:Aging, Premature / Q000473:pathology*; D000818:Animals; D015536:Down-Regulation / Q000187:drug effects; D005355:Fibrosis; D006801:Humans; D066298:In Vitro Techniques; D050356:Lipid Metabolism / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D009133:Muscular Atrophy / Q000473:pathology; D012038:Regeneration / Q000187:drug effects; D015203:Reproducibility of Results; D012518:Sarcomeres / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D026362:Serum Response Factor / Q000172:deficiency* / Q000235:genetics; D013629:Tamoxifen / Q000008:administration & dosage / Q000494:pharmacology
D026362:Serum Response Factor; D013629:Tamoxifen