Lung injury-induced skeletal muscle wasting in aged mice is linked to alterations in long chain fatty acid metabolism
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Older patients are more likely to acquire and die from acute respiratory distress syndrome (ARDS) and muscle weakness may be more clinically significant in older persons. Recent data implicate muscle ring finger protein 1 (MuRF1) in lung injury-induced skeletal muscle atrophy in young mice and identify an alternative role for MuRF1 in cardiac metabolism regulation through inhibition of fatty acid oxidation.
To develop a model of lung injury-induced muscle wasting in old mice and to evaluate the skeletal muscle metabolomic profile of adult and old acute lung injury (ALI) mice.
Young (2 month), adult (6 month) and old (20 month) male C57Bl6 J mice underwent Sham (intratracheal H2O) or ALI [intratracheal E. coli lipopolysaccharide (i.t. LPS)] conditions and muscle functional testing. Metabolomic analysis on gastrocnemius muscle was performed using gas chromatography-mass spectrometry (GC–MS).
Old ALI mice had increased mortality and failed to recover skeletal muscle function compared to adult ALI mice. Muscle MuRF1 expression was increased in old ALI mice at day 3. Non-targeted muscle metabolomics revealed alterations in amino acid biosynthesis and fatty acid metabolism in old ALI mice. Targeted metabolomics of fatty acid intermediates (acyl-carnitines) and amino acids revealed a reduction in long chain acyl-carnitines in old ALI mice.
This study demonstrates age-associated susceptibility to ALI-induced muscle wasting which parallels a metabolomic profile suggestive of altered muscle fatty acid metabolism. MuRF1 activation may contribute to both atrophy and impaired fatty acid oxidation, which may synergistically impair muscle function in old ALI mice.
KeywordsAging Muscle atrophy Metabolomics Acute respiratory distress syndrome Intensive care unit acquired weakness Fatty acid metabolism MuRF1
Acute lung injury
Acute respiratory distress syndrome
Extensor digitorum longus
This work was supported by the National Institutes of Health (R01HL104129 to M.W. and R01AG13934 to O.D.), the Leducq Foundation Transatlantic Networks of Excellence (to M.W.), the Claude D. Pepper Older Americans Independence Center (P30AG21332 to D.C.F and O.D.), and the American Thoracic Society Foundation (D.C.F.).
Compliance with ethical standards
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
Conflict of interest
The authors declare that they have no conflict of interest.
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