Depletion of HuR in murine skeletal muscle enhances exercise endurance and prevents cancer-induced muscle atrophy

Author:

Janice Sánchez Brenda,Tremblay Anne-Marie K.,Leduc-Gaudet Jean-PhilippeORCID,Hall Derek T.ORCID,Kovacs Erzsebet,Ma Jennifer F.ORCID,Mubaid Souad,Hallauer Patricia L.,Phillips Brittany L.,Vest Katherine E.,Corbett Anita H.ORCID,Kontoyiannis Dimitris L.,Hussain Sabah N. A.,Hastings Kenneth E. M.,Di Marco Sergio,Gallouzi Imed-Eddine

Abstract

Abstract The master posttranscriptional regulator HuR promotes muscle fiber formation in cultured muscle cells. However, its impact on muscle physiology and function in vivo is still unclear. Here, we show that muscle-specific HuR knockout (muHuR-KO) mice have high exercise endurance that is associated with enhanced oxygen consumption and carbon dioxide production. muHuR-KO mice exhibit a significant increase in the proportion of oxidative type I fibers in several skeletal muscles. HuR mediates these effects by collaborating with the mRNA decay factor KSRP to destabilize the PGC-1α mRNA. The type I fiber-enriched phenotype of muHuR-KO mice protects against cancer cachexia-induced muscle loss. Therefore, our study uncovers that under normal conditions HuR modulates muscle fiber type specification by promoting the formation of glycolytic type II fibers. We also provide a proof-of-principle that HuR expression can be targeted therapeutically in skeletal muscles to combat cancer-induced muscle wasting.

Funder

Gouvernement du Canada | Instituts de Recherche en Santé du Canada | CIHR Skin Research Training Centre

Canadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canada

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry

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