Philipp Du Bois1, Cristina Pablo Tortola1, Doerte Lodka1, Melanie Kny1, Franziska Schmidt1, Kunhua Song1, Sibylle Schmidt1, Rhonda Bassel-Duby1, Eric N Olson1, Jens Fielitz2. 1. From the Department of Molecular Cardiology, Experimental and Clinical Research Center (ECRC), a Cooperation between Max-Delbrück-Centrum and Charité Universitätsmedizin Berlin, Campus Buch, Berlin, Germany (P.D.B., C.P.T., D.L., M.K., F.S., S.S., J.F.); Department of Cardiology, Charité Universitätsmedizin Berlin, Campus Virchow, Berlin, Germany (J.F.); and Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas (K.S., R.B.-D., E.N.O.). 2. From the Department of Molecular Cardiology, Experimental and Clinical Research Center (ECRC), a Cooperation between Max-Delbrück-Centrum and Charité Universitätsmedizin Berlin, Campus Buch, Berlin, Germany (P.D.B., C.P.T., D.L., M.K., F.S., S.S., J.F.); Department of Cardiology, Charité Universitätsmedizin Berlin, Campus Virchow, Berlin, Germany (J.F.); and Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas (K.S., R.B.-D., E.N.O.). jens.fielitz@charite.de.
Abstract
RATIONALE: Skeletal muscle wasting with accompanying cachexia is a life threatening complication in congestive heart failure. The molecular mechanisms are imperfectly understood, although an activated renin-angiotensin aldosterone system 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 D1 (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 small interfering RNA prevented Ang II-induced MuRF1 expression and atrophy. The histone deacetylase-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. CONCLUSION: We propose that elevated Ang II serum concentrations, as occur in patients with congestive heart failure, could activate the PKD1/HDAC5/TFEB/MuRF1 pathway to induce skeletal muscle wasting.
RATIONALE: Skeletal muscle wasting with accompanying cachexia is a life threatening complication in congestive heart failure. The molecular mechanisms are imperfectly understood, although an activated renin-angiotensin aldosterone system 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 D1 (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 humanMuRF1 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 small interfering RNA prevented Ang II-induced MuRF1 expression and atrophy. The histone deacetylase-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. CONCLUSION: We propose that elevated Ang II serum concentrations, as occur in patients with congestive heart failure, could activate the PKD1/HDAC5/TFEB/MuRF1 pathway to induce skeletal muscle wasting.
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