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

Brenda Janice Sánchez, Anne-Marie K. Tremblay, Jean-Philippe Leduc-Gaudet, Derek T. Hall, Erzsebet Kovacs, Jennifer F. Ma, Souad Mubaid, Patricia L. Hallauer, Brittany L. Phillips, Katherine E. Vest, Anita H. Corbett, Dimitris L. Kontoyiannis, Sabah N. A. Hussain, Kenneth E. M. Hastings, Sergio Marco and Imed-Eddine Gallouzi ()
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Brenda Janice Sánchez: McGill University, 3655 Promenade Sir William Osler
Anne-Marie K. Tremblay: McGill University, 3655 Promenade Sir William Osler
Jean-Philippe Leduc-Gaudet: McGill University Health Centre Research Institute
Derek T. Hall: McGill University, 3655 Promenade Sir William Osler
Erzsebet Kovacs: Rosalind & Morris Goodman Cancer Research Center, McGill University, 3655 Promenade Sir William Osler
Jennifer F. Ma: McGill University, 3655 Promenade Sir William Osler
Souad Mubaid: McGill University, 3655 Promenade Sir William Osler
Patricia L. Hallauer: McGill University
Brittany L. Phillips: Emory University
Katherine E. Vest: University of Cincinnati College of Medicine, 231 Albert Sabin Way
Anita H. Corbett: Emory University
Dimitris L. Kontoyiannis: Biomedical Sciences Research Centre “Alexander Fleming”, Institute of Fundamental Biomedical Research
Sabah N. A. Hussain: McGill University Health Centre Research Institute
Kenneth E. M. Hastings: McGill University
Sergio Marco: McGill University, 3655 Promenade Sir William Osler
Imed-Eddine Gallouzi: McGill University, 3655 Promenade Sir William Osler

Nature Communications, 2019, vol. 10, issue 1, 1-17

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.

Date: 2019
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DOI: 10.1038/s41467-019-12186-6

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