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This Article Full Text (PDF) All Versions of this Article: 297/6/E1283    most recent ajpendo.00409.2009v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Sundaram, P. Articles by Wing, S. PubMed PubMed Citation Articles by Sundaram, P. Articles by Wing, S.

RESEARCH ARTICLE

USP19 Deubiquitinating Enzyme Regulates Levels of Major Myofibrillar Proteins in L6 Muscle Cells

¹Medicine, Polypeptide Laboratory and Biochemistry, McGill University ²Medicne, Polypeptide Laboratory, McGill Univeristy ³Medicine, Polypeptide Laboratory, McGill University ⁴Medicine, Polypeptide Laboratory and Biochemistry, McGill University and McGill University Health Centre, Strathcona Anatomy & Dentistry Bldg., 3640 University St., Room W315, Montreal, Quebec, H3A 2B2, Canada

Submitted 26 June 2009 ; revised 15 September 2009 ; accepted in final form 15 September 2009

The ubiquitin-proteasome system plays an important role in the degradation of myofibrillar proteins that occurs in muscle wasting. Many studies have demonstrated the importance of enzymes mediating conjugation of ubiquitin. However, little is known about the role of deubiquitinating enzymes. We previously showed that the USP19 deubiquitinating enzyme is induced in atrophying skeletal muscle (Combaret et al. Amer. J. Physiol. 2005; 288: E693-E700). To further explore the role of USP19, we used siRNA in L6 muscle cells. Lowering USP19 by 70-90% in myotubes resulted in a 20% decrease in the rate of proteolysis and an 18% decrease in the rate of protein synthesis with no net change in protein content. Despite the decrease in overall synthesis, there were ~1.5 fold increases in protein levels of myosin heavy chain (MHC), actin, troponin T and a ~2.5 fold increase in tropomyosin. USP19 depletion also increased MHC and tropomyosin mRNA levels suggesting that this effect is due to increased transcription. Consistent with this, USP19 depletion increased myogenin protein and mRNA levels by ~2 fold. Lowering myogenin using siRNA prevented the increase in MHC and tropomyosin upon USP19 depletion indicating that myogenin mediated the increase in myofibrillar proteins. Dexamethasone treatment lowered MHC and increased USP19. Depletion of USP19 reversed the dexamethasone suppression of MHC. These studies demonstrate that USP19 modulates transcription of major myofibrillar proteins and indicate that the ubiquitin system not only mediates the increased protein breakdown but is also involved in the decreased protein synthesis in atrophying skeletal muscle.

USP19; deubiquitinating enzyme; muscle wasting; glucocorticoids; myosin heavy chain