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Angiotensin II induces skeletal muscle atrophy by activating TFEB-mediated MuRF1 expression

Item Type:Article
Title:Angiotensin II induces skeletal muscle atrophy by activating TFEB-mediated MuRF1 expression
Creators Name:Du Bois, P. and Pablo Tortola, C. and Lodka, D. and Kny, M. and Schmidt, F. and Song, K. and Schmidt, S. and Bassel-Duby, R. and Olson, E.N. and Fielitz, J.
Abstract:RATIONALE: Skeletal-muscle wasting with accompanying cachexia is a life threatening complication in congestive heart failure (CHF). The molecular mechanisms are imperfectly understood, although an activated renin-angiotensin aldosterone system (RAAS) has been implicated. Angiotensin (Ang) II induces skeletal muscle atrophy in part by increased muscle-enriched E3 ubiquitin ligase muscle RING-finger-1 (MuRF1) expression, which may involve protein kinase-D (PKD1). OBJECTIVE: To elucidate the molecular mechanism of Ang II-induced skeletal muscle wasting. METHODS AND RESULTS: A cDNA expression screen identified the lysosomal hydrolase-coordinating transcription factor EB (TFEB) as novel regulator of the human MuRF1 promoter. TFEB played a key role in regulating Ang II-induced skeletal muscle atrophy by transcriptional control of MuRF1 via conserved E-box elements. Inhibiting TFEB with siRNA prevented Ang II induced MuRF1 expression and atrophy. The histone deactylase-5 (HDAC5), which was directly bound to and colocalized with TFEB, inhibited TFEB-induced MuRF1 expression. The inhibition of TFEB by HDAC5 was reversed by PKD1, which was associated with HDAC5 and mediated its nuclear export. Mice lacking PKD1 in skeletal myocytes were resistant to Ang II-induced muscle wasting. CONCLUSIONS: We propose that elevated Ang II serum concentrations, as occur in CHF patients, could activate the PKD1/HDAC5/TFEB/MuRF1 pathway to induce skeletal muscle wasting.
Keywords:Angiotensin II, Gene Expression Regulation, Heart Failure, Histone Deacetylase 5, Muscle RING-Finger-1, Protein Kinase D, Transcription Factor EB, Animals, Mice
Source:Circulation Research
Publisher:American Heart Association
Page Range:424-436
Date:14 August 2015
Official Publication:https://doi.org/10.1161/CIRCRESAHA.114.305393
PubMed:View item in PubMed

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