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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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Phenotype of dKO mice at 18 months of age. Perinatally, dKO mice have a high mortality of 74%. The 26% of dKO mice (n=27) that survived became long-term survivors and were all alive at month 18 (unless killed, see below), thus allowing phenotypic studies in aged dKO. (A) MRI scans detected hypertrophic hearts in adult dKO mice with reduced EFs and stroke volumes (for time-resolved MRI scans, see also Supplementary Videos 4, 5, 6 and 7). LV, left ventricle; RV, right ventricle; EDV, end-diastolic volume; ESV, end-systolic volume (total number of mice scanned: two mice of each genotype. (B) Left: effect of MuRF1/2 genotypes on heart (ventricles, left) and quadriceps skeletal muscle (right) to body weight ratios. dKO mice maintain cardiac hypertrophy during ageing (dKO, 84% increase, P=0.001; MuRF1, 24.5% increase; MuRF2, 19%). In addition, dKO mice have 38.1% increased QW/BW ratios (P=0.001), whereas MuRF1 KO and MuRF2 KO genotypes have moderate effects on skeletal muscle mass (MuRF1, 16% increase, P=0.05; MuRF2, 11% increase, P=0.08). Despite increasing body mass in WT during months 4–18, skeletal muscles remain more hypertrophic in dKO mice during ageing (4–18 months of age, dKO n=27; MuRF1 KO n=52; MuRF2 KO n=81; WT n=49). For absolute weights, please refer to Supplementary Figure 8. Right: hematoxylin/eosin sections indicated that skeletal myofibers from dKO muscle show hypertrophic fibers with slightly augmented cross-section areas alternating with normal-appearing fibers (mice aged 4 months). Scale bar, 100 μm. (C) Weight gain of WT and dKO mice during ageing. Left: between months 4–18, dKO mice gain less weight (red; P<0.001) than WT. Right: dissections revealed that aged dKO mice were leaner (mice aged 18 months).
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f2: Phenotype of dKO mice at 18 months of age. Perinatally, dKO mice have a high mortality of 74%. The 26% of dKO mice (n=27) that survived became long-term survivors and were all alive at month 18 (unless killed, see below), thus allowing phenotypic studies in aged dKO. (A) MRI scans detected hypertrophic hearts in adult dKO mice with reduced EFs and stroke volumes (for time-resolved MRI scans, see also Supplementary Videos 4, 5, 6 and 7). LV, left ventricle; RV, right ventricle; EDV, end-diastolic volume; ESV, end-systolic volume (total number of mice scanned: two mice of each genotype. (B) Left: effect of MuRF1/2 genotypes on heart (ventricles, left) and quadriceps skeletal muscle (right) to body weight ratios. dKO mice maintain cardiac hypertrophy during ageing (dKO, 84% increase, P=0.001; MuRF1, 24.5% increase; MuRF2, 19%). In addition, dKO mice have 38.1% increased QW/BW ratios (P=0.001), whereas MuRF1 KO and MuRF2 KO genotypes have moderate effects on skeletal muscle mass (MuRF1, 16% increase, P=0.05; MuRF2, 11% increase, P=0.08). Despite increasing body mass in WT during months 4–18, skeletal muscles remain more hypertrophic in dKO mice during ageing (4–18 months of age, dKO n=27; MuRF1 KO n=52; MuRF2 KO n=81; WT n=49). For absolute weights, please refer to Supplementary Figure 8. Right: hematoxylin/eosin sections indicated that skeletal myofibers from dKO muscle show hypertrophic fibers with slightly augmented cross-section areas alternating with normal-appearing fibers (mice aged 4 months). Scale bar, 100 μm. (C) Weight gain of WT and dKO mice during ageing. Left: between months 4–18, dKO mice gain less weight (red; P<0.001) than WT. Right: dissections revealed that aged dKO mice were leaner (mice aged 18 months).

Mentions: Those dKO mice that survived the first two postnatal weeks became long-term survivors: All dKO mice alive at week 3 (n=27; 26% of total dKO offspring) were still alive at month 18 (unless being killed for our studies) and were able to have offspring. Adult dKO mice maintain cardiac hypertrophy (dKO: 84% increase, P=0.001; see Figure 2B). Consistent with this, electrocardiography indicated intact excitation conduction in dKO hearts from aged mice (see Supplementary Figure 3; contrasting, for example, the conduction blocks observed in Nkx2.5 KO mice; see Pashmforoush et al, 2004). Next, we examined the physiological cardiac performance by MRI imaging in more detail. This indicated massive persistent hypertrophy (see Figure 2A). Next, we estimated ejection fractions (EF) and stroke volumes by time-resolved MRI. This showed grossly reduced EFs (dKO: 0.2–0.3; wild type (WT): 0.7; see Figure 2A), whereas stroke volumes were 26% reduced under basal conditions.


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)

Phenotype of dKO mice at 18 months of age. Perinatally, dKO mice have a high mortality of 74%. The 26% of dKO mice (n=27) that survived became long-term survivors and were all alive at month 18 (unless killed, see below), thus allowing phenotypic studies in aged dKO. (A) MRI scans detected hypertrophic hearts in adult dKO mice with reduced EFs and stroke volumes (for time-resolved MRI scans, see also Supplementary Videos 4, 5, 6 and 7). LV, left ventricle; RV, right ventricle; EDV, end-diastolic volume; ESV, end-systolic volume (total number of mice scanned: two mice of each genotype. (B) Left: effect of MuRF1/2 genotypes on heart (ventricles, left) and quadriceps skeletal muscle (right) to body weight ratios. dKO mice maintain cardiac hypertrophy during ageing (dKO, 84% increase, P=0.001; MuRF1, 24.5% increase; MuRF2, 19%). In addition, dKO mice have 38.1% increased QW/BW ratios (P=0.001), whereas MuRF1 KO and MuRF2 KO genotypes have moderate effects on skeletal muscle mass (MuRF1, 16% increase, P=0.05; MuRF2, 11% increase, P=0.08). Despite increasing body mass in WT during months 4–18, skeletal muscles remain more hypertrophic in dKO mice during ageing (4–18 months of age, dKO n=27; MuRF1 KO n=52; MuRF2 KO n=81; WT n=49). For absolute weights, please refer to Supplementary Figure 8. Right: hematoxylin/eosin sections indicated that skeletal myofibers from dKO muscle show hypertrophic fibers with slightly augmented cross-section areas alternating with normal-appearing fibers (mice aged 4 months). Scale bar, 100 μm. (C) Weight gain of WT and dKO mice during ageing. Left: between months 4–18, dKO mice gain less weight (red; P<0.001) than WT. Right: dissections revealed that aged dKO mice were leaner (mice aged 18 months).
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f2: Phenotype of dKO mice at 18 months of age. Perinatally, dKO mice have a high mortality of 74%. The 26% of dKO mice (n=27) that survived became long-term survivors and were all alive at month 18 (unless killed, see below), thus allowing phenotypic studies in aged dKO. (A) MRI scans detected hypertrophic hearts in adult dKO mice with reduced EFs and stroke volumes (for time-resolved MRI scans, see also Supplementary Videos 4, 5, 6 and 7). LV, left ventricle; RV, right ventricle; EDV, end-diastolic volume; ESV, end-systolic volume (total number of mice scanned: two mice of each genotype. (B) Left: effect of MuRF1/2 genotypes on heart (ventricles, left) and quadriceps skeletal muscle (right) to body weight ratios. dKO mice maintain cardiac hypertrophy during ageing (dKO, 84% increase, P=0.001; MuRF1, 24.5% increase; MuRF2, 19%). In addition, dKO mice have 38.1% increased QW/BW ratios (P=0.001), whereas MuRF1 KO and MuRF2 KO genotypes have moderate effects on skeletal muscle mass (MuRF1, 16% increase, P=0.05; MuRF2, 11% increase, P=0.08). Despite increasing body mass in WT during months 4–18, skeletal muscles remain more hypertrophic in dKO mice during ageing (4–18 months of age, dKO n=27; MuRF1 KO n=52; MuRF2 KO n=81; WT n=49). For absolute weights, please refer to Supplementary Figure 8. Right: hematoxylin/eosin sections indicated that skeletal myofibers from dKO muscle show hypertrophic fibers with slightly augmented cross-section areas alternating with normal-appearing fibers (mice aged 4 months). Scale bar, 100 μm. (C) Weight gain of WT and dKO mice during ageing. Left: between months 4–18, dKO mice gain less weight (red; P<0.001) than WT. Right: dissections revealed that aged dKO mice were leaner (mice aged 18 months).
Mentions: Those dKO mice that survived the first two postnatal weeks became long-term survivors: All dKO mice alive at week 3 (n=27; 26% of total dKO offspring) were still alive at month 18 (unless being killed for our studies) and were able to have offspring. Adult dKO mice maintain cardiac hypertrophy (dKO: 84% increase, P=0.001; see Figure 2B). Consistent with this, electrocardiography indicated intact excitation conduction in dKO hearts from aged mice (see Supplementary Figure 3; contrasting, for example, the conduction blocks observed in Nkx2.5 KO mice; see Pashmforoush et al, 2004). Next, we examined the physiological cardiac performance by MRI imaging in more detail. This indicated massive persistent hypertrophy (see Figure 2A). Next, we estimated ejection fractions (EF) and stroke volumes by time-resolved MRI. This showed grossly reduced EFs (dKO: 0.2–0.3; wild type (WT): 0.7; see Figure 2A), whereas stroke volumes were 26% reduced under basal conditions.

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