Skeletal Muscle Parvin Regulates Exercise Tolerance and Glucose Homeostasis in Mice
Authors: Lark Daniel Stephen , Kwan Jamie R. , Lantier Louise , Zent Roy , Pozzi Ambra , Wasserman David H. 
Published: June 2021

Integrins are a family of cell surface receptors that bind to the extracellular matrix (ECM). ECM‐integrin connections are necessary for skeletal muscle (SkM) contractile function, but also contribute to diet‐induced insulin resistance (IR). Parvins are key proteins in the integrin signaling pathway, with α‐parvin being the most highly expressed in SkM. α‐parvin is a critical regulator of cytoskeletal dynamics needed for organelle and protein function and localization within the cell; however, its function in SkM in vivo has not been previously explored. In these studies, we tested the hypothesis that SkM α‐parvin is a requisite component of the ECM‐integrin signaling that regulates exercise tolerance and glucose homeostasis.SkM‐specific α‐parvin knockout mice (mPar‐KO) were generated using α‐parvin floxed mice and mice expressing Cre recombinase on the human α‐skeletal actin (HSA) promoter. Studies were performed on littermate α‐parvin flox/flox mice with (KO) or without (WT) Cre recombinase. Fasting blood glucose was measured at 6 weeks of age in chow‐fed mice. At 12 weeks of age, oral glucose tolerance testing (2 g/kg bodyweight) was performed on 5‐hr fasted chow or 6‐week high fat diet (HFD; 60% calories from fat) fed mice. Whole body indirect calorimetry and contextual behavior mapping of lean and HFD‐fed mice was performed at 18 weeks of age in a Promethion Metabolic Analyzer. In a cohort of 18‐week old chow‐fed mice, forced exercise performance was assessed using a graded treadmill stress test and voluntary wheel running (VWR) distance and efficiency (kcal/m traveled) were measured during indirect calorimetry experiments.6‐week old mPar‐KO mice had normal body composition but fasting hyperglycemia compared to WT littermates (n=15/group). 12‐week old chow‐fed mPar‐KO mice were glucose intolerant despite normal fasting glucose (n=5/group). No differences in fasting glucose or glucose tolerance were observed in HF‐fed WT or mPar‐KO mice (n=16–18/group). Forced exercise performance was reduced in mPar‐KO mice. Furthermore, VWR distance was ~80% lower in mPar‐KO mice (n=7–9/group). mPar‐KO mice also had an increased metabolic cost of exercise during VWR that was accompanied by longer bouts of off‐wheel roaming. mPar‐KO mice with a running wheel had an elevated respiratory quotient at rest, indicating increased fat utilization. HFD‐fed mPar‐KO mice had no differences in metabolism or activity compared to WT littermates.These data demonstrate that loss of SkM α‐parvin impairs exercise tolerance and elicits an increase in resting whole body reliance on fatty acids. In contrast to previous studies showing that SkM integrins contribute to diet‐induced IR, these data demonstrate that SkM α‐parvin is necessary for maintaining normal glucose homeostasis in chow‐fed mice and does not contribute to HFD‐induced IR. Collectively, these experiments suggest that SkM α‐parvin is a point of divergence for the beneficial effects of ECM‐integrin connections on exercise and deleterious effects on glucose homeostasis.Support or Funding InformationD.S.L. (AHA 16POST29910001); D.H.W. (NIH DK054902, DK059637 and DK076169).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.