Restricted physical activity after volumetric muscle loss alters whole-body and local muscle metabolism

Christiana J. Raymond-Pope, Alec M. Basten, Angela S. Bruzina, Jennifer McFaline-Figueroa, Thomas J. Lillquist, Jarrod A. Call, Sarah M. Greising

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


Abstract: Volumetric muscle loss (VML) is the traumatic loss of skeletal muscle, resulting in chronic functional deficits and pathological comorbidities, including altered whole-body metabolic rate and respiratory exchange ratio (RER), despite no change in physical activity in animal models. In other injury models, treatment with β2 receptor agonists (e.g. formoterol) improves metabolic and skeletal muscle function. We aimed first to examine if restricting physical activity following injury affects metabolic and skeletal muscle function, and second, to enhance the metabolic and contractile function of the muscle remaining following VML injury through treatment with formoterol. Adult male C57Bl/6J mice (n = 32) underwent VML injury to the posterior hindlimb compartment and were randomly assigned to unrestricted or restricted activity and formoterol treatment or no treatment; age-matched injury naïve mice (n = 4) were controls for biochemical analyses. Longitudinal 24 h evaluations of physical activity and whole-body metabolism were conducted following VML. In vivo muscle function was assessed terminally, and muscles were biochemically evaluated for protein expression, mitochondrial enzyme activity and untargeted metabolomics. Restricting activity chronically after VML had the greatest effect on physical activity and RER, reflected in reduced lipid oxidation, although changes were attenuated by formoterol treatment. Formoterol enhanced injured muscle mass, while mitigating functional deficits. These novel findings indicate physical activity restriction may recapitulate following VML clinically, and adjunctive oxidative treatment may create a metabolically beneficial intramuscular environment while enhancing the injured muscle's mass and force-producing capacity. Further investigation is needed to evaluate adjunctive oxidative treatment with rehabilitation, which may augment the muscle's regenerative and functional capacity following VML. (Figure presented.). Key points: The natural ability of skeletal muscle to regenerate and recover function is lost following complex traumatic musculoskeletal injury, such as volumetric muscle loss (VML), and physical inactivity following VML may incur additional deleterious consequences for muscle and metabolic health. Modelling VML injury-induced physical activity restriction altered whole-body metabolism, primarily by decreasing lipid oxidation, while preserving local skeletal muscle metabolic activity. The β2 adrenergic receptor agonist formoterol has shown promise in other severe injury models to improve regeneration, recover function and enhance metabolism. Treatment with formoterol enhanced mass of the injured muscle and whole-body metabolism while mitigating functional deficits resulting from injury. Understanding of chronic effects of the clinically available and FDA-approved pharmaceutical formoterol could be a translational option to support muscle function after VML injury.

Original languageEnglish (US)
Pages (from-to)743-761
Number of pages19
JournalJournal of Physiology
Issue number4
StatePublished - Feb 15 2023

Bibliographical note

Funding Information:
Funding was through the Congressionally Directed Medical Research Program, Clinical & Rehabilitative Medicine Research Program: W81XWH-18-1-0710 (J.A.C. and S.M.G.), and the National Institutes of Health R01-AR078903 (J.A.C. and S.M.G.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. The opinions, interpretations, conclusions and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense or the National Institutes of Health. The authors thank the Center for Metabolomics and Proteomics at the University of Minnesota for providing services related to performing quantitative assays and statistical analyses for metabolite characterization.

Publisher Copyright:
© 2022 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.


  • formoterol
  • metabolic flexibility
  • orthopaedic trauma
  • physical inactivity
  • skeletal muscle injury
  • β Adrenergic receptor agonist

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.


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