Muscle RING-finger 2 and 3 maintain striated-muscle structure and function

Dörte Lodka, Aanchal Pahuja, Cornelia Geers-Knörr, Renate J. Scheibe, Marcel Nowak, Jida Hamati, Clemens Köhncke, Bettina Purfürst, Tamara Kanashova, Sibylle Schmidt, David J. Glass, Ingo Morano, Arnd Heuser, Theresia Kraft, Rhonda Bassel-Duby, Eric N. Olson, Gunnar Dittmar, Thomas Sommer, Jens Fielitz

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Background: 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. Methods: 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. Results: 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. Conclusions: The redundant function of MuRF2 and MuRF3 is important for maintenance of skeletal muscle and cardiac structure and function in vivo.

Original languageEnglish (US)
JournalJournal of Cachexia, Sarcopenia and Muscle
DOIs
StateAccepted/In press - 2015

Fingerprint

Striated Muscle
Knockout Mice
Fingers
Skeletal Muscle
Muscles
Maintenance
Sarcomeres
Ubiquitin-Protein Ligases
Myosin Heavy Chains
Muscular Diseases
Immunoblotting
Cardiac Myocytes
Microtubules
Echocardiography
Real-Time Polymerase Chain Reaction
Mass Spectrometry
Electron Microscopy
Protein Isoforms
Cell Culture Techniques
Calcium

Keywords

  • Heart failure
  • MAPKAPK
  • MuRF2
  • MuRF3
  • Protein homeostasis
  • Protein surplus myopathy

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine
  • Physiology (medical)

Cite this

Lodka, D., Pahuja, A., Geers-Knörr, C., Scheibe, R. J., Nowak, M., Hamati, J., ... Fielitz, J. (Accepted/In press). Muscle RING-finger 2 and 3 maintain striated-muscle structure and function. Journal of Cachexia, Sarcopenia and Muscle. https://doi.org/10.1002/jcsm.12057

Muscle RING-finger 2 and 3 maintain striated-muscle structure and function. / Lodka, Dörte; Pahuja, Aanchal; Geers-Knörr, Cornelia; Scheibe, Renate J.; Nowak, Marcel; Hamati, Jida; Köhncke, Clemens; Purfürst, Bettina; Kanashova, Tamara; Schmidt, Sibylle; Glass, David J.; Morano, Ingo; Heuser, Arnd; Kraft, Theresia; Bassel-Duby, Rhonda; Olson, Eric N.; Dittmar, Gunnar; Sommer, Thomas; Fielitz, Jens.

In: Journal of Cachexia, Sarcopenia and Muscle, 2015.

Research output: Contribution to journalArticle

Lodka, D, Pahuja, A, Geers-Knörr, C, Scheibe, RJ, Nowak, M, Hamati, J, Köhncke, C, Purfürst, B, Kanashova, T, Schmidt, S, Glass, DJ, Morano, I, Heuser, A, Kraft, T, Bassel-Duby, R, Olson, EN, Dittmar, G, Sommer, T & Fielitz, J 2015, 'Muscle RING-finger 2 and 3 maintain striated-muscle structure and function', Journal of Cachexia, Sarcopenia and Muscle. https://doi.org/10.1002/jcsm.12057
Lodka, Dörte ; Pahuja, Aanchal ; Geers-Knörr, Cornelia ; Scheibe, Renate J. ; Nowak, Marcel ; Hamati, Jida ; Köhncke, Clemens ; Purfürst, Bettina ; Kanashova, Tamara ; Schmidt, Sibylle ; Glass, David J. ; Morano, Ingo ; Heuser, Arnd ; Kraft, Theresia ; Bassel-Duby, Rhonda ; Olson, Eric N. ; Dittmar, Gunnar ; Sommer, Thomas ; Fielitz, Jens. / Muscle RING-finger 2 and 3 maintain striated-muscle structure and function. In: Journal of Cachexia, Sarcopenia and Muscle. 2015.
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abstract = "Background: 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. Methods: 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. Results: 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. Conclusions: The redundant function of MuRF2 and MuRF3 is important for maintenance of skeletal muscle and cardiac structure and function in vivo.",
keywords = "Heart failure, MAPKAPK, MuRF2, MuRF3, Protein homeostasis, Protein surplus myopathy",
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T1 - Muscle RING-finger 2 and 3 maintain striated-muscle structure and function

AU - Lodka, Dörte

AU - Pahuja, Aanchal

AU - Geers-Knörr, Cornelia

AU - Scheibe, Renate J.

AU - Nowak, Marcel

AU - Hamati, Jida

AU - Köhncke, Clemens

AU - Purfürst, Bettina

AU - Kanashova, Tamara

AU - Schmidt, Sibylle

AU - Glass, David J.

AU - Morano, Ingo

AU - Heuser, Arnd

AU - Kraft, Theresia

AU - Bassel-Duby, Rhonda

AU - Olson, Eric N.

AU - Dittmar, Gunnar

AU - Sommer, Thomas

AU - Fielitz, Jens

PY - 2015

Y1 - 2015

N2 - Background: 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. Methods: 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. Results: 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. Conclusions: The redundant function of MuRF2 and MuRF3 is important for maintenance of skeletal muscle and cardiac structure and function in vivo.

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KW - Heart failure

KW - MAPKAPK

KW - MuRF2

KW - MuRF3

KW - Protein homeostasis

KW - Protein surplus myopathy

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