Myosin accumulation and striated muscle myopathy result from the loss of muscle RING finger 1 and 3

Jens Fielitz, Mi Sung Kim, John M. Shelton, Shuaib Latif, Jeffrey A. Spencer, David J. Glass, James A. Richardson, Rhonda Bassel-Duby, Eric N. Olson

Research output: Contribution to journalArticle

160 Citations (Scopus)

Abstract

Maintenance of skeletal and cardiac muscle structure and function requires precise control of the synthesis, assembly, and turnover of contractile proteins of the sarcomere. Abnormalities in accumulation of sarcomere proteins are responsible for a variety of myopathies. However, the mechanisms that mediate turnover of these long-lived proteins remain poorly defined. We show that muscle RING finger 1 (MuRF1) and MuRF3 act as E3 ubiquitin ligases that cooperate with the E2 ubiquitin-conjugating enzymes UbcH5a, -b, and -c to mediate the degradation of β/slow myosin heavy chain (β/slow MHC) and MHCIIa via the ubiquitin proteasome system (UPS) in vivo and in vitro. Accordingly, mice deficient for MuRF1 and MuRF3 develop a skeletal muscle myopathy and hypertrophic cardiomyopathy characterized by subsarcolemmal MHC accumulation, myofiber fragmentation, and diminished muscle performance. These findings identify MuRF1 and MuRF3 as key E3 ubiquitin ligases for the UPS-dependent turnover of sarcomeric proteins and reveal a potential basis for myosin storage myopathies.

Original languageEnglish (US)
Pages (from-to)2486-2495
Number of pages10
JournalJournal of Clinical Investigation
Volume117
Issue number9
DOIs
StatePublished - Sep 4 2007

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Striated Muscle
Muscular Diseases
Myosins
Muscles
Sarcomeres
Ubiquitin-Protein Ligases
Proteasome Endopeptidase Complex
Ubiquitin
Skeletal Muscle
Ubiquitin-Conjugating Enzymes
Contractile Proteins
Proteins
Myosin Heavy Chains
Hypertrophic Cardiomyopathy
Myocardium
Maintenance

ASJC Scopus subject areas

  • Medicine(all)

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Myosin accumulation and striated muscle myopathy result from the loss of muscle RING finger 1 and 3. / Fielitz, Jens; Kim, Mi Sung; Shelton, John M.; Latif, Shuaib; Spencer, Jeffrey A.; Glass, David J.; Richardson, James A.; Bassel-Duby, Rhonda; Olson, Eric N.

In: Journal of Clinical Investigation, Vol. 117, No. 9, 04.09.2007, p. 2486-2495.

Research output: Contribution to journalArticle

Fielitz, Jens ; Kim, Mi Sung ; Shelton, John M. ; Latif, Shuaib ; Spencer, Jeffrey A. ; Glass, David J. ; Richardson, James A. ; Bassel-Duby, Rhonda ; Olson, Eric N. / Myosin accumulation and striated muscle myopathy result from the loss of muscle RING finger 1 and 3. In: Journal of Clinical Investigation. 2007 ; Vol. 117, No. 9. pp. 2486-2495.
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AU - Spencer, Jeffrey A.

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AU - Olson, Eric N.

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