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Am J Respir Crit Care Med. 2012 Apr 15;185(8):825-34. doi: 10.1164/rccm.201106-1150OC. Epub 2012 Feb 3.

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

Author information

1
Division of Pulmonary and Critical Care Medicine, Johns Hopkins Asthma and Allergy Center, Baltimore, Maryland, USA.

Abstract

RATIONALE:

Acute lung injury (ALI) is a debilitating condition associated with severe skeletal muscle weakness that persists 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 associated with reduced muscle 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 in ALI mice and that, as in humans, skeletal muscle dysfunction persists despite resolution of lung injury.

PMID:
22312013
PMCID:
PMC3360571
DOI:
10.1164/rccm.201106-1150OC
[Indexed for MEDLINE]
Free PMC Article

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