title: Angiotensin II Induces Skeletal Muscle Atrophy by Activating TFEB-Mediated MuRF1 Expression.
abstract: BACKGROUND
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.).
authors.forename: Philipp
authors.initials: P
authors.lastname: Du Bois
authors.affiliation: 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.).
authors.forename: Cristina
authors.initials: C
authors.lastname: Pablo Tortola
authors.affiliation: 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.).
authors.forename: Doerte
authors.initials: D
authors.lastname: Lodka
authors.affiliation: 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.).
authors.forename: Melanie
authors.initials: M
authors.lastname: Kny
authors.affiliation: 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.).
authors.forename: Franziska
authors.initials: F
authors.lastname: Schmidt
authors.affiliation: 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.).
authors.forename: Kunhua
authors.initials: K
authors.lastname: Song
authors.affiliation: 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.).
authors.forename: Sibylle
authors.initials: S
authors.lastname: Schmidt
authors.affiliation: 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.).
authors.forename: Rhonda
authors.initials: R
authors.lastname: Bassel-Duby
authors.affiliation: 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.).
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
authors.affiliation: 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.
authors.forename: Jens
authors.initials: J
authors.lastname: Fielitz
mesh_terms: D000804:Angiotensin II / Q000633:toxicity*; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000096:biosynthesis*; D009133:Muscular Atrophy / Q000139:chemically induced* / Q000378:metabolism*; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D009124:Muscle Proteins; C064972:TFEB protein, human; D000070584:Tripartite Motif Proteins; D000804:Angiotensin II; C440908:TRIM63 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: angiotensin II; gene expression regulation; heart failure; histone deacetylase 5; muscle RING-finger-1; protein kinase D; transcription factor EB