Muscle function recovery after acute lung injury is impaired in aged mice, linked in part, to metabolic alterations attributed to MuRF1 by quantitative targeted metabolomics analysis of acyl‐carnitines

Abstract

Most survivors of acute lung injury suffer from substantial physical complications months after the initial lung injury resolves, and persistent muscle weakness is a very common sequelae of lung injury. Using a mouse model of LPS‐induced lung injury [acute lung injury (ALI) mice], we found that old (20 month) ALI mice failed to recover skeletal muscle function 10 days after injury compared to young (6 month) ALI control mice. Non‐targeted GC‐MS analysis of old ALI gastrocnemius muscle vs. vehicle treated controls identified 18 significantly different metabolites, including the long chain fatty acid linoleic acid (1.75 fold increased), indicative of altered linoleic acid metabolism. Our laboratory recently identified that muscle ring finger protein 1 (MuRF1) inhibits fatty acid oxidation in vivo via mono‐ubiquitination of peroxisome proliferator‐activated receptor alpha. Moreover, we've identified that MuRF1−/− mice are resistant to LPS‐induced muscle atrophy. Western analysis of old and young ALI muscles for MuRF1 found significantly greater expression of MuRF1 3 days following lung injury in old ALI mice, leading us to hypothesize that old ALI muscles had inhibited fatty acid oxidation. We next performed targeted metabolomics analysis of fatty acid intermediates (acyl‐carnitines) and amino acids of the affected muscles. At day 10, we identified 13 significantly altered acyl carnitines (by t‐test, p<0.05) compared to vehicle treated controls (0.27–1.14 fold). We also identified that total long chain acyl‐carnitines were almost decreased by half, paralleling the acyl‐carnitine profile recently published in MuRF1−/− hearts. Together, these studies demonstrate for the first time age‐associated susceptibility of ALI‐induced muscle wasting and characterize the metabolic alterations in fatty acid metabolism, suggesting MuRF1's role in regulating fatty acid metabolism, which may contribute to impaired skeletal muscle functional recovery.Support or Funding InformationThis work was supported by the National Institutes of Health (R01HL104129 to M.W.), 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.).