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Cooperative control of striated muscle mass and metabolism by MuRF1 and MuRF2.

Witt CC, Witt SH, Lerche S, Labeit D, Back W, Labeit S - EMBO J. (2007)

Bottom Line: The muscle-specific RING finger proteins MuRF1 and MuRF2 have been proposed to regulate protein degradation and gene expression in muscle tissues.Muscle hypertrophy in dKO mice was maintained throughout the murine life span and was associated with chronically activated muscle protein synthesis.Other catabolic factors such as MAFbox/atrogin1 were expressed at normal levels and did not respond to or prevent muscle hypertrophy in dKO mice.

View Article: PubMed Central - PubMed

Affiliation: Institute of Anesthesiology and Intensive Care, Universitätsklinikum Mannheim, Mannheim, Germany.

ABSTRACT
The muscle-specific RING finger proteins MuRF1 and MuRF2 have been proposed to regulate protein degradation and gene expression in muscle tissues. We have tested the in vivo roles of MuRF1 and MuRF2 for muscle metabolism by using knockout (KO) mouse models. Single MuRF1 and MuRF2 KO mice are healthy and have normal muscles. Double knockout (dKO) mice obtained by the inactivation of all four MuRF1 and MuRF2 alleles developed extreme cardiac and milder skeletal muscle hypertrophy. Muscle hypertrophy in dKO mice was maintained throughout the murine life span and was associated with chronically activated muscle protein synthesis. During ageing (months 4-18), skeletal muscle mass remained stable, whereas body fat content did not increase in dKO mice as compared with wild-type controls. Other catabolic factors such as MAFbox/atrogin1 were expressed at normal levels and did not respond to or prevent muscle hypertrophy in dKO mice. Thus, combined inhibition of MuRF1/MuRF2 could provide a potent strategy to stimulate striated muscles anabolically and to protect muscles from sarcopenia during ageing.

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Related in: MedlinePlus

Altered Z-disks and mitochondrial ultrastructure in dKO myocardium. (A, B) At 18 months, we noted no ultrastructural abnormalities in myocardium from WT (A), MuRF1-KO (B), and MuRF2 KO (not shown) mice. (C, D) In dKO myocardium, sarcomere lengths and myofiber alignments are less regular (maximal variation is 2.5-fold larger than in WT sarcomeres). Z-disks have a denser appearance (arrows). Vacuoles (V) are frequently found between or embedded within mitochondria (M). Mitochondria are less regular in shape including abnormally small mitochondria and are, unlike in WT, not tightly packed together. Scale bar, 1 μm.
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f4: Altered Z-disks and mitochondrial ultrastructure in dKO myocardium. (A, B) At 18 months, we noted no ultrastructural abnormalities in myocardium from WT (A), MuRF1-KO (B), and MuRF2 KO (not shown) mice. (C, D) In dKO myocardium, sarcomere lengths and myofiber alignments are less regular (maximal variation is 2.5-fold larger than in WT sarcomeres). Z-disks have a denser appearance (arrows). Vacuoles (V) are frequently found between or embedded within mitochondria (M). Mitochondria are less regular in shape including abnormally small mitochondria and are, unlike in WT, not tightly packed together. Scale bar, 1 μm.

Mentions: Because MuRF1 and MuRF2 interact with multiple components of the Z-disk and of the mitochondrium (Figure 3A), we studied the ultrastructural effects of the absence of MuRF1 and MuRF2 on Z-disks and mitochondria in myocardium by electron microscopy. We were unable to detect differences between WT, MuRF1, and MuRF2-KO myocardium (Figure 4A and B). In contrast, myofibrils in dKO myocardium were abnormal: myofibrils had more electron-dense Z-disks and were less regular (Figure 4C and D). Occasionally, myofibrils assembled in dKO hearts had free ends, somewhat reminiscent of growth tips found in proliferating skeletal myotubes (Ojima et al, 1999), and projected into regions rich in unassembled free filaments (not shown).


Cooperative control of striated muscle mass and metabolism by MuRF1 and MuRF2.

Witt CC, Witt SH, Lerche S, Labeit D, Back W, Labeit S - EMBO J. (2007)

Altered Z-disks and mitochondrial ultrastructure in dKO myocardium. (A, B) At 18 months, we noted no ultrastructural abnormalities in myocardium from WT (A), MuRF1-KO (B), and MuRF2 KO (not shown) mice. (C, D) In dKO myocardium, sarcomere lengths and myofiber alignments are less regular (maximal variation is 2.5-fold larger than in WT sarcomeres). Z-disks have a denser appearance (arrows). Vacuoles (V) are frequently found between or embedded within mitochondria (M). Mitochondria are less regular in shape including abnormally small mitochondria and are, unlike in WT, not tightly packed together. Scale bar, 1 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2168395&req=5

f4: Altered Z-disks and mitochondrial ultrastructure in dKO myocardium. (A, B) At 18 months, we noted no ultrastructural abnormalities in myocardium from WT (A), MuRF1-KO (B), and MuRF2 KO (not shown) mice. (C, D) In dKO myocardium, sarcomere lengths and myofiber alignments are less regular (maximal variation is 2.5-fold larger than in WT sarcomeres). Z-disks have a denser appearance (arrows). Vacuoles (V) are frequently found between or embedded within mitochondria (M). Mitochondria are less regular in shape including abnormally small mitochondria and are, unlike in WT, not tightly packed together. Scale bar, 1 μm.
Mentions: Because MuRF1 and MuRF2 interact with multiple components of the Z-disk and of the mitochondrium (Figure 3A), we studied the ultrastructural effects of the absence of MuRF1 and MuRF2 on Z-disks and mitochondria in myocardium by electron microscopy. We were unable to detect differences between WT, MuRF1, and MuRF2-KO myocardium (Figure 4A and B). In contrast, myofibrils in dKO myocardium were abnormal: myofibrils had more electron-dense Z-disks and were less regular (Figure 4C and D). Occasionally, myofibrils assembled in dKO hearts had free ends, somewhat reminiscent of growth tips found in proliferating skeletal myotubes (Ojima et al, 1999), and projected into regions rich in unassembled free filaments (not shown).

Bottom Line: The muscle-specific RING finger proteins MuRF1 and MuRF2 have been proposed to regulate protein degradation and gene expression in muscle tissues.Muscle hypertrophy in dKO mice was maintained throughout the murine life span and was associated with chronically activated muscle protein synthesis.Other catabolic factors such as MAFbox/atrogin1 were expressed at normal levels and did not respond to or prevent muscle hypertrophy in dKO mice.

View Article: PubMed Central - PubMed

Affiliation: Institute of Anesthesiology and Intensive Care, Universitätsklinikum Mannheim, Mannheim, Germany.

ABSTRACT
The muscle-specific RING finger proteins MuRF1 and MuRF2 have been proposed to regulate protein degradation and gene expression in muscle tissues. We have tested the in vivo roles of MuRF1 and MuRF2 for muscle metabolism by using knockout (KO) mouse models. Single MuRF1 and MuRF2 KO mice are healthy and have normal muscles. Double knockout (dKO) mice obtained by the inactivation of all four MuRF1 and MuRF2 alleles developed extreme cardiac and milder skeletal muscle hypertrophy. Muscle hypertrophy in dKO mice was maintained throughout the murine life span and was associated with chronically activated muscle protein synthesis. During ageing (months 4-18), skeletal muscle mass remained stable, whereas body fat content did not increase in dKO mice as compared with wild-type controls. Other catabolic factors such as MAFbox/atrogin1 were expressed at normal levels and did not respond to or prevent muscle hypertrophy in dKO mice. Thus, combined inhibition of MuRF1/MuRF2 could provide a potent strategy to stimulate striated muscles anabolically and to protect muscles from sarcopenia during ageing.

Show MeSH
Related in: MedlinePlus