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

• Type of Material: Article
• Authors: Grace Pavlath, Emory University; Brenda Janice Sanchez, McGill University; Anne-Marie K. Tremblay, McGill University; Jean-Philippe Leduc-Gaudet, McGill University; Derek T. Hall, McGill University; Erzsebet Kovacs, McGill University; Jennifer F. Ma, McGill University; Souad Mubaid, McGill University; Patricia L. Hallauer, McGill University; Brittany L. Phillips, Emory University; Katherine E. Vest, University of Cincinnati; Anita Corbett, Emory University; Dimitris L. Kontoyiannis, Institute of Fundamental Biomedical Research; Sabah N. A. Hussain, McGill University; Kenneth E. M. Hastings, McGill University; Sergio Di Marco, McGill University; Imed-Eddine Gallouzi, McGill University
• Language: English
• Date: 2019-09-13
• Publisher: Nature Research (part of Springer Nature): Fully open access journals
• Publication Version: Final Published Version
• Copyright Statement: © 2019, The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-019-12186-6
• Title of Journal or Parent Work: Nature Communications
• ISSN: 2041-1723
• Volume: 10
• Issue: 1
• Start Page: 4171
• End Page: 4171
• Grant/Funding Information: B.J.S was funded by a scholarship received from the Concejo Nacional de Ciencia y Tecnologia (CONACyT); the Fonds de recherche du Québec— Nature et technologies (FRQNT); and the Biochemistry department at McGill University.; J.F.M. was supported by the CIHR/FRSQ training grant in cancer research of the McGill Integrated Cancer Research Training Program.; D.T.H. was funded by a scholarship received from the Canadian Institute of Health Research (CIHR) funded Chemical Biology Program at McGill University.; This work is funded by CIHR operating grants (MOP‐142399, MOP-89798); and a NSERC Discovery grant RGPIN-2014–06035 to I.E.G.
• Keywords: FIBER-TYPE SPECIFICITY; GENE MYF-5; PHOSPHORYLATION; Science & Technology - Other Topics; PGC-1-ALPHA; PROTEIN; INACTIVATION; Multidisciplinary Sciences; MYOD; MESSENGER-RNA; METABOLISM; Science & Technology; MOLECULAR REGULATION
• Research Categories: Biology, General; Chemistry, Biochemistry

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.