title: Muscle RING-finger 2 and 3 maintain striated-muscle structure and function.
abstract: The Muscle-specific RING-finger (MuRF) protein family of E3 ubiquitin ligases is important for maintenance of muscular structure and function. MuRF proteins mediate adaptation of striated muscles to stress. MuRF2 and MuRF3 bind to microtubules and are implicated in sarcomere formation with noticeable functional redundancy. However, if this redundancy is important for muscle function in vivo is unknown. Our objective was to investigate cooperative function of MuRF2 and MuRF3 in the skeletal muscle and the heart in vivo.
  
  
  
  MuRF2 and MuRF3 double knockout mice (DKO) were generated and phenotypically characterized. Skeletal muscle and the heart were investigated by morphological measurements, histological analyses, electron microscopy, immunoblotting, and real-time PCR. Isolated muscles were subjected to in vitro force measurements. Cardiac function was determined by echocardiography and working heart preparations. Function of cardiomyocytes was measured in vitro. Cell culture experiments and mass-spectrometry were used for mechanistic analyses.
  
  
  
  DKO mice showed a protein aggregate myopathy in skeletal muscle. Maximal force development was reduced in DKO soleus and extensor digitorum longus. Additionally, a fibre type shift towards slow/type I fibres occurred in DKO soleus and extensor digitorum longus. MuRF2 and MuRF3-deficient hearts showed decreased systolic and diastolic function. Further analyses revealed an increased expression of the myosin heavy chain isoform beta/slow and disturbed calcium handling as potential causes for the phenotype in DKO hearts.
  
  
  
  The redundant function of MuRF2 and MuRF3 is important for maintenance of skeletal muscle and cardiac structure and function in vivo.
authors: Department of Molecular Cardiology, Experimental and Clinical Research Center (ECRC) Max Delbrück Center for Molecular Medicine and Charité Universitätsmedizin Berlin, Campus Buch 13125 Berlin Germany.
authors: Dörte
authors: D
authors: Lodka
authors: Institute of Molecular and Cell Physiology Hannover Medical School 30625 Hannover Germany.
authors: Aanchal
authors: A
authors: Pahuja
authors: Institute of Molecular and Cell Physiology Hannover Medical School 30625 Hannover Germany.
authors: Cornelia
authors: C
authors: Geers-Knörr
authors: Institute of Physiological Chemistry Hannover Medical School 30625 Hannover Germany.
authors: Renate J
authors: RJ
authors: Scheibe
authors: Department of Molecular Cardiology, Experimental and Clinical Research Center (ECRC) Max Delbrück Center for Molecular Medicine and Charité Universitätsmedizin Berlin, Campus Buch 13125 Berlin Germany; Department of Intracellular Proteolysis Max Delbrück Center for Molecular Medicine 13125 Berlin Germany.
authors: Marcel
authors: M
authors: Nowak
authors: Department of Molecular Cardiology, Experimental and Clinical Research Center (ECRC) Max Delbrück Center for Molecular Medicine and Charité Universitätsmedizin Berlin, Campus Buch 13125 Berlin Germany.
authors: Jida
authors: J
authors: Hamati
authors: Department of Molecular Muscle Physiology Max Delbrück Center for Molecular Medicine 13125 Berlin Germany.
authors: Clemens
authors: C
authors: Köhncke
authors: Department of Electron Microscopy Max Delbrück Center for Molecular Medicine 13125 Berlin Germany.
authors: Bettina
authors: B
authors: Purfürst
authors: Department of Mass Spectrometry Max Delbrück Center for Molecular Medicine 13125 Berlin Germany.
authors: Tamara
authors: T
authors: Kanashova
authors: Department of Molecular Cardiology, Experimental and Clinical Research Center (ECRC) Max Delbrück Center for Molecular Medicine and Charité Universitätsmedizin Berlin, Campus Buch 13125 Berlin Germany.
authors: Sibylle
authors: S
authors: Schmidt
authors: Novartis Institutes for Biomedical Research Cambridge Massachusetts 02139 USA.
authors: David J
authors: DJ
authors: Glass
authors: Department of Molecular Muscle Physiology Max Delbrück Center for Molecular Medicine 13125 Berlin Germany.
authors: Ingo
authors: I
authors: Morano
authors: Department of Cardiovascular Molecular Genetics Max Delbrück Center for Molecular Medicine 13125 Berlin Germany.
authors: Arnd
authors: A
authors: Heuser
authors: Institute of Molecular and Cell Physiology Hannover Medical School 30625 Hannover Germany.
authors: Theresia
authors: T
authors: Kraft
authors: Department of Molecular Biology University of Texas Southwestern Medical Center Dallas Texas 75390-9148 USA.
authors: Rhonda
authors: R
authors: Bassel-Duby
authors: Department of Molecular Biology University of Texas Southwestern Medical Center Dallas Texas 75390-9148 USA.
authors: Eric N
authors: EN
authors: Olson
authors: Department of Mass Spectrometry Max Delbrück Center for Molecular Medicine 13125 Berlin Germany.
authors: Gunnar
authors: G
authors: Dittmar
authors: Department of Intracellular Proteolysis Max Delbrück Center for Molecular Medicine 13125 Berlin Germany.
authors: Thomas
authors: T
authors: Sommer
authors: Department of Molecular Cardiology, Experimental and Clinical Research Center (ECRC) Max Delbrück Center for Molecular Medicine and Charité Universitätsmedizin Berlin, Campus Buch 13125 Berlin Germany; Department of Cardiology Charité Universitätsmedizin Berlin, Campus Virchow 13353 Berlin Germany.
authors: Jens
authors: J
authors: Fielitz
keywords: Heart failure; MAPKAPK; MuRF2; MuRF3; Protein homeostasis; Protein surplus myopathy