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

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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 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).

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.

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Abbreviations

ALI:

Acute lung injury

ARDS:

Acute respiratory distress syndrome

LPS:

Lipopolysaccharide

GAS:

Gastrocnemius

EDL:

Extensor digitorum longus

SOL:

Soleus

TA:

Tibialis anterior

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Acknowledgments

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.).

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Author notes

    Authors and Affiliations

    1. 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

      D. Clark Files

    2. Internal Medicine-Section in Pulmonary and Critical Care Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA

      Kevin W. Gibbs & Chun Liu

    3. Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA

      Amro Ilaiwy, James R. Bain & Michael J. Muehlbauer

    4. Internal Medicine-Geriatrics, Wake Forest School of Medicine, Winston-Salem, NC, USA

      Osvaldo Delbono

    5. Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, Duke University Medical Center, Durham, NC, USA

      Amro Ilaiwy & James R. Bain

    6. McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA

      Traci L. Parry

    7. Department of Pharmacology, McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA

      Monte S. Willis

    8. Department of Pathology and Laboratory Medicine, McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA

      Monte S. Willis

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    1. D. Clark Files
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    D. C. Files and A. Ilaiwy have contributed equally.

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    11306_2016_1079_MOESM1_ESM.pdf

    Supplemental Figure 1. Enrichment analysis of significant non-targeted metabolomics analysis of adult (6 month) gastrocnemius tissue 10 days post ALI or Sham. Enrichment by A) Disease-associated metabolite sets in the blood. B) Disease associated metabolite sets in CSF, and C) Location-Based Metabolite sets determined from VIP significant and t-test significant metabolites identified. Supplemental Figure 2. Enrichment analysis of significant non-targeted metabolomics analysis of old (20 month) gastrocnemius tissue 10 days post ALI or Sham Enrichment by A) Disease-associated metabolite sets in the blood. B) Disease associated metabolite sets in CSF, and C) Location-Based Metabolite sets determined from VIP significant and t-test significant metabolites identified. Supplemental Figure 3. AGE-dependent and ALI-dependent metabolites found by non-targeted metabolomics analysis. A) Significant AGE-dependent metabolites (including metabolites altered in all old vs sham, but not in adult ALI) and ALI-Dependent metabolites (Significantly different in all ALI, but not in Old or Adult Sham). B) Normalized peak values of the AGE-dependent docosahexanoic acid (DHA) among the four groups studied. C) Normalized peak values of the ALI-dependent linoleic acid among the four groups studied. No significant alterations in linoleic acid levels were detected between adult and old Sham mice by post hoc test. *p<0.05 vs. ALI adult, ^p<0.05 vs Sham old. #p<0.05 vs Sham adult. +p<0.05 vs Sham adult. N=10/group. Supplemental Figure 4. Significantly altered acyl-carnitine species in old gastrocnemius tissue 10 days post-ALI demonstrating the specific inhibition of long chain acyl-carnitines. X axis represents fatty acid chain length, measured by number of carbons in their structure. Acylcarnitines above the dotted green line had higher concentration in ALI mice compared to Sham. Acylcarnitines with 2-5 carbons in their structure were considered short. Acylcarnitines with 6-12 carbons were considered medium, and acylcarntines with 14-22 carbons were considered long. A Student’s T-test was used to determine significance between groups, with significance defined as p<0.05. Supplemental Figure 5. Targeted acyl-carnitine profile of old ALI muscle reveals significant decreases in long chain acyl carnitine (C14-C22), paralleling the phenotype seen in cardiac muscle with increased MuRF1 expression. A) Heat map of the One-Way ANOVA significant acyl-carnitines, determined by Fisher LSD post hoc test results. Fisher LSD post hoc comparisons were made to Sham adult muscle. Mean of each metabolite level in control groups was standardized to 1, and metabolite levels in experimental groups were then normalized to their control mean. Metabolites identified were later used to plot acyl carnitine concentration curve in each model. B) Box and whisker plot of total long chain acyl-carnitines using normalized concentrations measured by targeted metabolomics among eight groups of comparison. *p<0.05 MuRF1-/- vs. ALI adult, +p<0.05 MuRF1-/- vs. ALI old, $p<0.05 MuRF1-/- vs MuRF1 Tg+, #p<0.05 ALI old vs Sham old, ^p<0.05 ALI old vs Sham adult. C) Fold change of acyl-carnitine concentrations in mice normalized to their controls. X axis represents fatty acid chain length, measured by number of carbons in their structure. Y axis represents acyl-carnitine fold change. Each exponential line represents acyl-carnitine fold change in its specific group, with identified acyl-carnitines plotted in panel. Only significantly altered acyl-carnitines in Fisher LSD post hoc results among all groups were dot-plotted in this figure (p<0.05). D) ANOVA significant acyl-carnitine species. Long chain acyl-carnitines defined as C14-C22; Medium chain acyl-carnitines defined as C6-C13; Short chain acyl-carnitines C2-C5. N=10/adult Sham, adult ALI, old Sham, old ALI, N=3/WildtypeMuRF1Tg+, MuRF1 Tg+, N=4/MuRF1+/+, MuRF1-/-. Significance was defined as p<0.05. Supplemental Figure 6. Pathway enrichment analysis of ALI-dependent metabolites, determined by non-targeted metabolomics. a-c indicates top pathways identified, along with the specific significant metabolites found that placed it in this category. ALI dependent metabolites determined by Fisher LSD post hoc results were used in the pathway enrichment analysis. Of note, pathway enrichment analysis of Age dependent metabolites (urea, docosahexanoic acid) was also performed, but no altered pathways were detected. (PDF 1553 kb)

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    Files, D.C., Ilaiwy, A., Parry, T.L. et al. Lung injury-induced skeletal muscle wasting in aged mice is linked to alterations in long chain fatty acid metabolism. Metabolomics 12, 134 (2016). https://doi.org/10.1007/s11306-016-1079-5

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