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


OBJECTIVE
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.


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.
Division of Pulmonary and Critical Care Medicine, Johns Hopkins Asthma and Allergy Center, Baltimore, Maryland, USA.
D Clark
DC
Files
Franco R
FR
D'Alessio
Laura F
LF
Johnston
Priya
P
Kesari
Neil R
NR
Aggarwal
Brian T
BT
Garibaldi
Jason R
JR
Mock
Jessica L
JL
Simmers
Antonio
A
DeGorordo
Jared
J
Murdoch
Monte S
MS
Willis
Cam
C
Patterson
Clarke G
CG
Tankersley
Maria L
ML
Messi
Chun
C
Liu
Osvaldo
O
Delbono
J David
JD
Furlow
Sue C
SC
Bodine
Ronald D
RD
Cohn
Landon S
LS
King
Michael T
MT
Crow
D055371:Acute Lung Injury / Q000235:genetics* / Q000473:pathology*; D000818:Animals; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D004195:Disease Models, Animal; D015536:Down-Regulation; D005786:Gene Expression Regulation; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015999:Multivariate Analysis; D009124:Muscle Proteins / Q000235:genetics*; D053580:Muscle Strength / Q000502:physiology; D018482:Muscle, Skeletal / Q000473:pathology / Q000503:physiopathology; D009133:Muscular Atrophy / Q000235:genetics* / Q000473:pathology; D054829:RING Finger Domains / Q000235:genetics; D011897:Random Allocation; D012680:Sensitivity and Specificity; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
D009124:Muscle Proteins; D000070584:Tripartite Motif Proteins; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases