Modulation of Klotho expression in injured muscle perturbs Wnt signalling and influences the rate of muscle growth
New Findings What is the central question of this study? Does modulating the expression of Klotho affect myogenesis following acute injury of healthy, non‐senescent muscle? What is the main finding and its importance? Klotho can accelerate muscle growth following acute injury of healthy, adult mice,...
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Published in | Experimental physiology Vol. 105; no. 1; pp. 132 - 147 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
England
John Wiley & Sons, Inc
01.01.2020
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Subjects | |
Online Access | Get full text |
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Summary: | New Findings
What is the central question of this study?
Does modulating the expression of Klotho affect myogenesis following acute injury of healthy, non‐senescent muscle?
What is the main finding and its importance?
Klotho can accelerate muscle growth following acute injury of healthy, adult mice, which supports the possibility that increased delivery of Klotho could have therapeutic value for improving repair of damaged muscle.
Skeletal muscle injuries activate a complex programme of myogenesis that can restore normal muscle structure. We tested whether modulating the expression of klotho influenced the response of mouse muscles to acute injury. Our findings show that klotho expression in muscle declines at 3 days post‐injury. That reduction in klotho expression coincided with elevated expression of targets of Wnt signalling (Ccnd1; Myc) and increased MyoD+ muscle cell numbers, reflecting the onset of myogenic cell differentiation. klotho expression subsequently increased at 7 days post‐injury with elevated expression occurring primarily in inflammatory lesions, which was accompanied by reduced expression of Wnt target genes (Ccnd1: 91%; Myc: 96%). Introduction of a klotho transgene maintained high levels of klotho expression over the course of muscle repair and attenuated the increases in Ccnd1 and Myc expression that occurred at 3 days post‐injury. Correspondingly, transgene expression reduced Wnt signalling in Pax7+ cells, reflected by reductions in Pax7+ cells expressing active β‐catenin, and reduced the numbers of MyoD+ cells at 3 days post‐injury. At 21 days post‐injury, muscles in klotho transgenic mice showed increased Pax7+ and decreased myogenin+ cell densities and large increases in myofibre size. Likewise, treating myogenic cells in vitro with Klotho reduced Myod expression but did not affect Pax7 expression. Muscle inflammation was only slightly modulated by increased klotho expression, initially reducing the expression of M2‐biased macrophage markers Cd163 and Cd206 at 3 days post‐injury and later increasing the expression of pan‐macrophage marker F480 and Cd68 at 21 days post‐injury. Collectively, our study shows that Klotho modulates myogenesis and that increased expression accelerates muscle growth after injury. |
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Bibliography: | Funding information Research reported in this publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under award numbers F32AR065845 (to S.S.W.), and RO1AR066036 and RO1AR062579 (to J.G.T.). Edited by: Julien Ochala ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 James G. Tidball, 1135 Terasaki Life Science Building, Molecular, Cellular & Integrative Physiology Program, University of California, Los Angeles, CA 90095 Steven S. Welc, Indiana University School of Medicine, 635 Barnhill Drive, MS-332, Indianapolis, IN 46202, swelc@iu.edu Kyle A. Thomas, Box 957239, 1162 Terasaki Life Science Building, Department of Integrative Biology and Physiology, University of California, Los Angeles, CA 90095, swelc@ucla.edu Author addresses AUTHOR CONTRIBUTIONS All authors contributed to the conception or design of the research. S.S.W., M.W-H and K.T. performed the experiments. M.K. generated the Klotho transgenic mouse line that is used in the investigation. S.S.W. and J.G.T. analyzed the data and wrote the manuscript. All authors approved the final version of the manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Makoto Kuro-o, Division of Anti-Aging Medicine, Center for Molecular Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan, mkuroo@jichi.ac.jp Michelle Wehling-Henricks, Box 957239, 1155 Terasaki Life Science Building, Department of Integrative Biology and Physiology, University of California, Los Angeles, CA 90095, henricks@physci.ucla.edu |
ISSN: | 0958-0670 1469-445X |
DOI: | 10.1113/EP088142 |