title: Lung injury-induced skeletal muscle wasting in aged mice is linked to alterations in long chain fatty acid metabolism.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  Young (2 month), adult (6 month) and old (20 month) male C57Bl6J mice underwent Sham (intratracheal H2O) or ALI [intratrachealE. colilipopolysaccharide (i.t. LPS)] conditions and muscle functional testing. Metabolomic analysis on gastrocnemius muscle was performed using gas chromatography-mass spectrometry (GC-MS).
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Internal Medicine-Sections in Pulmonary and Critical Care Medicine and Geriatrics and the Critical Illness Injury and Recovery Research Center, Wake Forest School of Medicine, Winston-Salem, NC USA.
authors.forename: D Clark
authors.initials: DC
authors.lastname: Files
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA; Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, Duke University Medical Center, Durham, NC, USA.
authors.forename: Amro
authors.initials: A
authors.lastname: Ilaiwy
authors.affiliation: McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Traci L
authors.initials: TL
authors.lastname: Parry
authors.affiliation: Internal Medicine-Section in Pulmonary and Critical Care Medicine.
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Gibbs
authors.affiliation: Internal Medicine-Section in Pulmonary and Critical Care Medicine.
authors.forename: Chun
authors.initials: C
authors.lastname: Liu
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA; Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, Duke University Medical Center, Durham, NC, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Bain
authors.affiliation: Internal Medicine-Geriatrics, Wake Forest School of Medicine, Winston-Salem, NC USA.
authors.forename: Osvaldo
authors.initials: O
authors.lastname: Delbono
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Muehlbauer
authors.affiliation: McAllister Heart Institute, Department of Pharmacology, Department of Pathology & Laboratory, Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Monte S
authors.initials: MS
authors.lastname: Willis
keywords: Aging; MuRF1; acute respiratory distress syndrome; fatty acid metabolism; intensive care unit acquired weakness; metabolomics; muscle atrophy