A Critical Role for Muscle Ring Finger-1 in Acute Lung Injury–associated Skeletal Muscle Wasting

Autor: Jessica L. Simmers, J. David Furlow, María Laura Messi, Michael T. Crow, Landon S. King, W. Cam Patterson, Neil R. Aggarwal, Jared Murdoch, Jason R. Mock, D. Clark Files, Priya Kesari, Antonio DeGorordo, Ronald D. Cohn, Osvaldo Delbono, Monte S. Willis, Brian T. Garibaldi, Sue C. Bodine, Chun Liu, Laura Johnston, Clarke G. Tankersley, Franco R. D'Alessio
Rok vydání: 2012
Předmět:
Male
Pulmonary and Respiratory Medicine
medicine.medical_specialty
Pathology
Ubiquitin-Protein Ligases
Acute Lung Injury
Blotting
Western
Down-Regulation
Muscle Proteins
Lung injury
Critical Care and Intensive Care Medicine
Sensitivity and Specificity
Tripartite Motif Proteins
Mice
Random Allocation
Atrophy
Downregulation and upregulation
Internal medicine
medicine
Animals
Muscle Strength
Muscle
Skeletal
Wasting
Regulation of gene expression
business.industry
Skeletal muscle
respiratory system
medicine.disease
Immunohistochemistry
Muscle atrophy
respiratory tract diseases
Mice
Inbred C57BL
Disease Models
Animal
Muscular Atrophy
Endocrinology
medicine.anatomical_structure
Gene Expression Regulation
Multivariate Analysis
medicine.symptom
RING Finger Domains
business
ITGA7
Bronchoalveolar Lavage Fluid
Zdroj: American Journal of Respiratory and Critical Care Medicine. 185:825-834
ISSN: 1535-4970
1073-449X
DOI: 10.1164/rccm.201106-1150oc
Popis: 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.
Databáze: OpenAIRE
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