Higher expression of denervation‐responsive genes is negatively associated with muscle volume and performance traits in the study of muscle, mobility, and aging (SOMMA)

Author:

Lukasiewicz Cole J.1,Tranah Gregory J.23,Evans Daniel S.23,Coen Paul M.4ORCID,Barnes Haley N.2,Huo Zhiguang5,Esser Karyn A.5ORCID,Zhang Xiping5,Wolff Christopher5,Wu Kevin5,Lane Nancy E.6,Kritchevsky Steven B.7,Newman Anne B.8,Cummings Steven R.23,Cawthon Peggy M.23,Hepple Russell T.15ORCID

Affiliation:

1. Department of Physical Therapy University of Florida Gainesville Florida USA

2. California Pacific Medical Center Research Institute San Francisco California USA

3. Department of Epidemiology and Biostatistics University of California San Francisco California USA

4. Translational Research Institute, Advent Health Orlando Florida USA

5. Department of Physiology and Aging University of Florida College of Medicine Gainesville Florida USA

6. Department of Medicine, Division of Rheumatology University of California Davis Health Sacramento California USA

7. Department of Internal Medicine Wake Forest University School of Medicine Winston‐Salem North Carolina USA

8. School of Public Health University of Pittsburgh Pittsburgh Pennsylvania USA

Abstract

AbstractWith aging skeletal muscle fibers undergo repeating cycles of denervation and reinnervation. In approximately the 8th decade of life reinnervation no longer keeps pace, resulting in the accumulation of persistently denervated muscle fibers that in turn cause an acceleration of muscle dysfunction. The significance of denervation in important clinical outcomes with aging is poorly studied. The Study of Muscle, Mobility, and Aging (SOMMA) is a large cohort study with the primary objective to assess how aging muscle biology impacts clinically important traits. Using transcriptomics data from vastus lateralis muscle biopsies in 575 participants we have selected 49 denervation‐responsive genes to provide insights to the burden of denervation in SOMMA, to test the hypothesis that greater expression of denervation‐responsive genes negatively associates with SOMMA participant traits that included time to walk 400 meters, fitness (VO2peak), maximal mitochondrial respiration, muscle mass and volume, and leg muscle strength and power. Consistent with our hypothesis, increased transcript levels of: a calciumdependent intercellular adhesion glycoprotein (CDH15), acetylcholine receptor subunits (CHRNA1, CHRND, CHRNE), a glycoprotein promoting reinnervation (NCAM1), a transcription factor regulating aspects of muscle organization (RUNX1), and a sodium channel (SCN5A) were each negatively associated with at least 3 of these traits. VO2peak and maximal respiration had the strongest negative associations with 15 and 19 denervation‐responsive genes, respectively. In conclusion, the abundance of denervationresponsive gene transcripts is a significant determinant of muscle and mobility outcomes in aging humans, supporting the imperative to identify new treatment strategies to restore innervation in advanced age.

Publisher

Wiley

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