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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

Synergistic control of heart muscle mass and cardiac myocyte size by MuRF1 and MuRF2. (A) Dissection of 13-day-old MuRF1 and MuRF2-dKO mice revealed grossly enlarged hearts (h), causing caudally lung compression (lu); the liver appears hyperaemic (li). (B) Effect of MuRF1/MuRF2 genotypes on heart weights. Left: hearts isolated from two matched pairs of WT and dKO mice (13 days old). Right: dKO mouse hearts (ventricles only) had 231% (P=0.001) increased HW/BW ratios, whereas weights of MuRF1, MuRF2 KO, and WT hearts did not differ significantly (young mice between d8 and d24; MuRF1: 25.5% increase, P=0.1, MuRF2: 27%, P=0.2, heart ventricles weights, respectively; dKO n=18; MuRF1 KO n=6, MuRF2 KO n=7; WT n=7). (C) Left: hematoxylin/eosin (HE) sections indicated that cardiomyocytes from young dKO hearts were hypertrophic. Scale bar, 20 μm. Right: morphometric comparison of WT and dKO sections nuclei had 59% increased length and cardiomyocytes were also 58% larger/cell density was reduced by 58% (as indicated by the number of cells in 0.2 mm2 large sections). (D) HE (top) and Masson histology (bottom) of WT and dKO hearts indicated concentric-type physiological hypertrophy at month 12, with intact inner and outer circular fiber systems and absence of fibrosis. Scale bar, 1 mm.
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f1: Synergistic control of heart muscle mass and cardiac myocyte size by MuRF1 and MuRF2. (A) Dissection of 13-day-old MuRF1 and MuRF2-dKO mice revealed grossly enlarged hearts (h), causing caudally lung compression (lu); the liver appears hyperaemic (li). (B) Effect of MuRF1/MuRF2 genotypes on heart weights. Left: hearts isolated from two matched pairs of WT and dKO mice (13 days old). Right: dKO mouse hearts (ventricles only) had 231% (P=0.001) increased HW/BW ratios, whereas weights of MuRF1, MuRF2 KO, and WT hearts did not differ significantly (young mice between d8 and d24; MuRF1: 25.5% increase, P=0.1, MuRF2: 27%, P=0.2, heart ventricles weights, respectively; dKO n=18; MuRF1 KO n=6, MuRF2 KO n=7; WT n=7). (C) Left: hematoxylin/eosin (HE) sections indicated that cardiomyocytes from young dKO hearts were hypertrophic. Scale bar, 20 μm. Right: morphometric comparison of WT and dKO sections nuclei had 59% increased length and cardiomyocytes were also 58% larger/cell density was reduced by 58% (as indicated by the number of cells in 0.2 mm2 large sections). (D) HE (top) and Masson histology (bottom) of WT and dKO hearts indicated concentric-type physiological hypertrophy at month 12, with intact inner and outer circular fiber systems and absence of fibrosis. Scale bar, 1 mm.

Mentions: Our MuRF1 and MuRF2 KO mouse models correspond both to constitutive models (for details on gene targeting, see Supplementary Figure 1B–D). The obtained MuRF1 and MuRF2 KO mice that are homozygous for MuRF1 or MuRF2 have normal fertility and are viable (consistent with Bodine et al, 2001; Willis et al, 2007). Also, deletion of MuRF1 or MuRF2 has no effect on life span until month 24 (our oldest MuRF1 or MuRF2 KO mice so far). Fertility of single MuRF1 or MuRF2 KO mice allowed the generation of dKO strains by breeding them together. Newborn dKO mice have a severe phenotype: 74% of mice homozygous for both MuRF1 and MuRF2 KO alleles die within the first 7–16 days of life. Dissection of these young dKO mice revealed grossly enlarged hearts that filled the entire mediastinum (Figure 1A and B).


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)

Synergistic control of heart muscle mass and cardiac myocyte size by MuRF1 and MuRF2. (A) Dissection of 13-day-old MuRF1 and MuRF2-dKO mice revealed grossly enlarged hearts (h), causing caudally lung compression (lu); the liver appears hyperaemic (li). (B) Effect of MuRF1/MuRF2 genotypes on heart weights. Left: hearts isolated from two matched pairs of WT and dKO mice (13 days old). Right: dKO mouse hearts (ventricles only) had 231% (P=0.001) increased HW/BW ratios, whereas weights of MuRF1, MuRF2 KO, and WT hearts did not differ significantly (young mice between d8 and d24; MuRF1: 25.5% increase, P=0.1, MuRF2: 27%, P=0.2, heart ventricles weights, respectively; dKO n=18; MuRF1 KO n=6, MuRF2 KO n=7; WT n=7). (C) Left: hematoxylin/eosin (HE) sections indicated that cardiomyocytes from young dKO hearts were hypertrophic. Scale bar, 20 μm. Right: morphometric comparison of WT and dKO sections nuclei had 59% increased length and cardiomyocytes were also 58% larger/cell density was reduced by 58% (as indicated by the number of cells in 0.2 mm2 large sections). (D) HE (top) and Masson histology (bottom) of WT and dKO hearts indicated concentric-type physiological hypertrophy at month 12, with intact inner and outer circular fiber systems and absence of fibrosis. Scale bar, 1 mm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: Synergistic control of heart muscle mass and cardiac myocyte size by MuRF1 and MuRF2. (A) Dissection of 13-day-old MuRF1 and MuRF2-dKO mice revealed grossly enlarged hearts (h), causing caudally lung compression (lu); the liver appears hyperaemic (li). (B) Effect of MuRF1/MuRF2 genotypes on heart weights. Left: hearts isolated from two matched pairs of WT and dKO mice (13 days old). Right: dKO mouse hearts (ventricles only) had 231% (P=0.001) increased HW/BW ratios, whereas weights of MuRF1, MuRF2 KO, and WT hearts did not differ significantly (young mice between d8 and d24; MuRF1: 25.5% increase, P=0.1, MuRF2: 27%, P=0.2, heart ventricles weights, respectively; dKO n=18; MuRF1 KO n=6, MuRF2 KO n=7; WT n=7). (C) Left: hematoxylin/eosin (HE) sections indicated that cardiomyocytes from young dKO hearts were hypertrophic. Scale bar, 20 μm. Right: morphometric comparison of WT and dKO sections nuclei had 59% increased length and cardiomyocytes were also 58% larger/cell density was reduced by 58% (as indicated by the number of cells in 0.2 mm2 large sections). (D) HE (top) and Masson histology (bottom) of WT and dKO hearts indicated concentric-type physiological hypertrophy at month 12, with intact inner and outer circular fiber systems and absence of fibrosis. Scale bar, 1 mm.
Mentions: Our MuRF1 and MuRF2 KO mouse models correspond both to constitutive models (for details on gene targeting, see Supplementary Figure 1B–D). The obtained MuRF1 and MuRF2 KO mice that are homozygous for MuRF1 or MuRF2 have normal fertility and are viable (consistent with Bodine et al, 2001; Willis et al, 2007). Also, deletion of MuRF1 or MuRF2 has no effect on life span until month 24 (our oldest MuRF1 or MuRF2 KO mice so far). Fertility of single MuRF1 or MuRF2 KO mice allowed the generation of dKO strains by breeding them together. Newborn dKO mice have a severe phenotype: 74% of mice homozygous for both MuRF1 and MuRF2 KO alleles die within the first 7–16 days of life. Dissection of these young dKO mice revealed grossly enlarged hearts that filled the entire mediastinum (Figure 1A and B).

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