Lung injury-induced skeletal muscle wasting in aged mice is linked to alterations in long chain fatty acid metabolism

Abstract

Introduction 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. Objectives 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 [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). 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. Conclusion 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.

Skeletal Muscle Wasting and Function Impairment in Intensive Care Patients With Severe COVID-19

“…Inflammation reduces muscle protein synthesis and increases muscle degradation ( Vesali et al, 2010 ). In clinical and experimental studies it has been shown that lung-derived inflammatory mediators are associated with muscle wasting in acute and chronic inflammatory lung disease ( de Godoy et al, 1996 ; Files et al, 2016 ). Currently, no studies have shown acute muscle wasting in patients with critical COVID-19.…”

Timing of valproic acid in acute lung injury: prevention is the best therapy?

“…1)? We have previously demonstrated an ameliorated inflammatory phenotype in a well validated and commonly used murine model of gram-negative pneumonia-induced acute lung injury 17–20 utilizing a broad-spectrum histone deacetylase inhibitor (HDACI), valproic acid (VPA), administered early. 21 HDACI is thought to exert at least part of their potent anti-inflammatory effects by interacting with the toll-like receptor, myeloid differentiation factor 88 (MyD88), interleukin-1 receptor kinase (IRAK1), and NF-kB pathway.…”

The Metabolome and Osteoarthritis: Possible Contributions to Symptoms and Pathology

“…Weak muscle strength is a risk factor for development and progression of knee OA [106,107]. In a mouse model of muscle wasting, gastrocnemius muscle showed changes in linoleic acid, lactate, serine, alanine, and long-chain acyl-carnitines, as measured by gas chromatography-mass spectrometry, compared to controls [66]. Several muscular dystrophy disorders also carry a variety of metabolite differences in muscle tissue, as measured using 1 H-NMR, including BCAAs, glutamine/glutamate, histidine, acetate, propionate, fumarate, and tyrosine [63].…”