A critical role for muscle ring finger-1 in acute lung injury-associated skeletal muscle wasting

D. Clark Files, Franco R. D'Alessio, Laura F. Johnston, Priya Kesari, Neil R. Aggarwal, Brian T. Garibaldi, Jason R. Mock, Jessica L. Simmers, Antonio DeGorordo, Jared Murdoch, Monte Willis, Cam Patterson, Clarke G. Tankersley, Maria L. Messi, Chun Liu, Osvaldo Delbono, J. David Furlow, Sue C. Bodine, Ronald D. Cohn, Landon S. KingMichael T. Crow

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

Rationale: Acute lung injury (ALI) is a debilitating condition associated with severe skeletal muscle weakness thatpersists in humans long after lung injury has resolved. The molecular mechanisms underlying this condition are unknown. Objectives: To identify the muscle-specific molecular mechanisms responsible for muscle wasting in a mouse model of ALI. Methods:Changes in skeletal muscle weight, fiber size, in vivo contractile performance, and expression of mRNAs and proteins encoding muscle atrophy-associated genes for muscle ring finger-1 (MuRF1) and atrogin1 were measured. Genetic inactivation of MuRF1 or electroporation-mediated transduction of miRNA-based short hairpin RNAs targeting either MuRF1 or atrogin1 were used to identify their role in ALI-associated skeletal muscle wasting. Measurements and Main Results: Mice with ALI developed profound muscle atrophy and preferential loss of muscle contractile proteins associatedwith reducedmuscle function in vivo. Although mRNA expression of the muscle-specific ubiquitin ligases, MuRF1 and atrogin1, was increased in ALI mice, only MuRF1 protein levels were up-regulated. Consistent with these changes, suppression of MuRF1 by genetic or biochemical approaches prevented muscle fiber atrophy, whereas suppression of atrogin1 expression was without effect. Despite resolution of lung injury and down-regulation of MuRF1 and atrogin1, force generation in ALI mice remained suppressed. Conclusions: These data show that MuRF1 is responsible for mediating muscle atrophy that occurs during the period of active lung injury inALI mice and that, as in humans, skeletal muscle dysfunction persists despite resolution of lung injury.

Original languageEnglish (US)
Pages (from-to)825-834
Number of pages10
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume185
Issue number8
DOIs
StatePublished - Apr 15 2012
Externally publishedYes

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Acute Lung Injury
Fingers
Skeletal Muscle
Muscles
Muscular Atrophy
Lung Injury
Contractile Proteins
Messenger RNA
Electroporation
Muscle Proteins
Skeletal Muscle Fibers
Muscle Weakness
Ligases
Ubiquitin
MicroRNAs
Small Interfering RNA
Molecular Biology
Proteins
Down-Regulation
Weights and Measures

Keywords

  • Critical illness myopathy
  • Intensive care unit-acquired weakness
  • Muscle atrophy genes
  • Proteasomal-mediated protein degradation
  • Skeletal muscle atrophy

ASJC Scopus subject areas

  • Medicine(all)
  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Files, D. C., D'Alessio, F. R., Johnston, L. F., Kesari, P., Aggarwal, N. R., Garibaldi, B. T., ... Crow, M. T. (2012). A critical role for muscle ring finger-1 in acute lung injury-associated skeletal muscle wasting. American Journal of Respiratory and Critical Care Medicine, 185(8), 825-834. https://doi.org/10.1164/rccm.201106-1150OC

A critical role for muscle ring finger-1 in acute lung injury-associated skeletal muscle wasting. / Files, D. Clark; D'Alessio, Franco R.; Johnston, Laura F.; Kesari, Priya; Aggarwal, Neil R.; Garibaldi, Brian T.; Mock, Jason R.; Simmers, Jessica L.; DeGorordo, Antonio; Murdoch, Jared; Willis, Monte; Patterson, Cam; Tankersley, Clarke G.; Messi, Maria L.; Liu, Chun; Delbono, Osvaldo; Furlow, J. David; Bodine, Sue C.; Cohn, Ronald D.; King, Landon S.; Crow, Michael T.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 185, No. 8, 15.04.2012, p. 825-834.

Research output: Contribution to journalArticle

Files, DC, D'Alessio, FR, Johnston, LF, Kesari, P, Aggarwal, NR, Garibaldi, BT, Mock, JR, Simmers, JL, DeGorordo, A, Murdoch, J, Willis, M, Patterson, C, Tankersley, CG, Messi, ML, Liu, C, Delbono, O, Furlow, JD, Bodine, SC, Cohn, RD, King, LS & Crow, MT 2012, 'A critical role for muscle ring finger-1 in acute lung injury-associated skeletal muscle wasting', American Journal of Respiratory and Critical Care Medicine, vol. 185, no. 8, pp. 825-834. https://doi.org/10.1164/rccm.201106-1150OC
Files, D. Clark ; D'Alessio, Franco R. ; Johnston, Laura F. ; Kesari, Priya ; Aggarwal, Neil R. ; Garibaldi, Brian T. ; Mock, Jason R. ; Simmers, Jessica L. ; DeGorordo, Antonio ; Murdoch, Jared ; Willis, Monte ; Patterson, Cam ; Tankersley, Clarke G. ; Messi, Maria L. ; Liu, Chun ; Delbono, Osvaldo ; Furlow, J. David ; Bodine, Sue C. ; Cohn, Ronald D. ; King, Landon S. ; Crow, Michael T. / A critical role for muscle ring finger-1 in acute lung injury-associated skeletal muscle wasting. In: American Journal of Respiratory and Critical Care Medicine. 2012 ; Vol. 185, No. 8. pp. 825-834.
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abstract = "Rationale: Acute lung injury (ALI) is a debilitating condition associated with severe skeletal muscle weakness thatpersists in humans long after lung injury has resolved. The molecular mechanisms underlying this condition are unknown. Objectives: To identify the muscle-specific molecular mechanisms responsible for muscle wasting in a mouse model of ALI. Methods:Changes in skeletal muscle weight, fiber size, in vivo contractile performance, and expression of mRNAs and proteins encoding muscle atrophy-associated genes for muscle ring finger-1 (MuRF1) and atrogin1 were measured. Genetic inactivation of MuRF1 or electroporation-mediated transduction of miRNA-based short hairpin RNAs targeting either MuRF1 or atrogin1 were used to identify their role in ALI-associated skeletal muscle wasting. Measurements and Main Results: Mice with ALI developed profound muscle atrophy and preferential loss of muscle contractile proteins associatedwith reducedmuscle function in vivo. Although mRNA expression of the muscle-specific ubiquitin ligases, MuRF1 and atrogin1, was increased in ALI mice, only MuRF1 protein levels were up-regulated. Consistent with these changes, suppression of MuRF1 by genetic or biochemical approaches prevented muscle fiber atrophy, whereas suppression of atrogin1 expression was without effect. Despite resolution of lung injury and down-regulation of MuRF1 and atrogin1, force generation in ALI mice remained suppressed. Conclusions: These data show that MuRF1 is responsible for mediating muscle atrophy that occurs during the period of active lung injury inALI mice and that, as in humans, skeletal muscle dysfunction persists despite resolution of lung injury.",
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AU - Files, D. Clark

AU - D'Alessio, Franco R.

AU - Johnston, Laura F.

AU - Kesari, Priya

AU - Aggarwal, Neil R.

AU - Garibaldi, Brian T.

AU - Mock, Jason R.

AU - Simmers, Jessica L.

AU - DeGorordo, Antonio

AU - Murdoch, Jared

AU - Willis, Monte

AU - Patterson, Cam

AU - Tankersley, Clarke G.

AU - Messi, Maria L.

AU - Liu, Chun

AU - Delbono, Osvaldo

AU - Furlow, J. David

AU - Bodine, Sue C.

AU - Cohn, Ronald D.

AU - King, Landon S.

AU - Crow, Michael T.

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Y1 - 2012/4/15

N2 - Rationale: Acute lung injury (ALI) is a debilitating condition associated with severe skeletal muscle weakness thatpersists in humans long after lung injury has resolved. The molecular mechanisms underlying this condition are unknown. Objectives: To identify the muscle-specific molecular mechanisms responsible for muscle wasting in a mouse model of ALI. Methods:Changes in skeletal muscle weight, fiber size, in vivo contractile performance, and expression of mRNAs and proteins encoding muscle atrophy-associated genes for muscle ring finger-1 (MuRF1) and atrogin1 were measured. Genetic inactivation of MuRF1 or electroporation-mediated transduction of miRNA-based short hairpin RNAs targeting either MuRF1 or atrogin1 were used to identify their role in ALI-associated skeletal muscle wasting. Measurements and Main Results: Mice with ALI developed profound muscle atrophy and preferential loss of muscle contractile proteins associatedwith reducedmuscle function in vivo. Although mRNA expression of the muscle-specific ubiquitin ligases, MuRF1 and atrogin1, was increased in ALI mice, only MuRF1 protein levels were up-regulated. Consistent with these changes, suppression of MuRF1 by genetic or biochemical approaches prevented muscle fiber atrophy, whereas suppression of atrogin1 expression was without effect. Despite resolution of lung injury and down-regulation of MuRF1 and atrogin1, force generation in ALI mice remained suppressed. Conclusions: These data show that MuRF1 is responsible for mediating muscle atrophy that occurs during the period of active lung injury inALI mice and that, as in humans, skeletal muscle dysfunction persists despite resolution of lung injury.

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KW - Critical illness myopathy

KW - Intensive care unit-acquired weakness

KW - Muscle atrophy genes

KW - Proteasomal-mediated protein degradation

KW - Skeletal muscle atrophy

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