A deletion in the myostatin gene causes the compact ( Cmpt ) hypermuscular mutation in mice

Szabó, Gyula; Dallmann, Géza; Müller, Géza; Patthy, László; Soller, M.; Varga, L.

doi:10.1007/s003359900843

Cited by 144 publications

(109 citation statements)

References 10 publications

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“…The BEH line is homozygous for the compact mutation (36) and is coded as Mstn ComptϪdl1ABC (37,38). Mice from the BEH line were crossed with mice from the Berlin Low line (BEL) to introduce the wild type back into the BEH mice, to allow segregation of the wild-type and the compact allele in this subline, coded BEH C/ϩ (35).…”

Section: Methodsmentioning

confidence: 99%

Lack of myostatin results in excessive muscle growth but impaired force generation

Amthor

Macharia

Olivares-Navarrete

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

341

317

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The lack of myostatin promotes growth of skeletal muscle, and blockade of its activity has been proposed as a treatment for various muscle-wasting disorders. Here, we have examined two independent mouse lines that harbor mutations in the myostatin gene, constitutive null ( Mstn −/− ) and compact (Berlin High Line, BEH c/c ). We report that, despite a larger muscle mass relative to age-matched wild types, there was no increase in maximum tetanic force generation, but that when expressed as a function of muscle size (specific force), muscles of myostatin-deficient mice were weaker than wild-type muscles. In addition, Mstn −/− muscle contracted and relaxed faster during a single twitch and had a marked increase in the number of type IIb fibers relative to wild-type controls. This change was also accompanied by a significant increase in type IIB fibers containing tubular aggregates. Moreover, the ratio of mitochondrial DNA to nuclear DNA and mitochondria number were decreased in myostatin-deficient muscle, suggesting a mitochondrial depletion. Overall, our results suggest that lack of myostatin compromises force production in association with loss of oxidative characteristics of skeletal muscle.

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Section: Methodsmentioning

confidence: 99%

Lack of myostatin results in excessive muscle growth but impaired force generation

Amthor

Macharia

Olivares-Navarrete

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

341

317

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“…Disruption of Mstn functionality results in increased muscle mass, decreased adiposity and improved efficiency (McPherron and Szabo et al, 1998;Yang et al, 2001;McPherron and Lee, 2002;Mitchell and Wall, 2007). Mstn null mice often exhibit muscle weights 1.5 to 2 times greater than their wild-type counterparts , whereas weights of individual fat pads are reduced (McPherron and Lee, 2002).…”

Section: Discussionmentioning

confidence: 99%

The myostatin null mutation and clenbuterol administration elicit additive effects in mice

Dilger

Gabriel

Kutzler

et al. 2010

Animal

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In mice, the myostatin (Mstn) null mutation and treatment with clenbuterol both increase muscle growth and decrease fat mass. Our objective was to determine whether mechanistic overlap exists by administering clenbuterol to Mstn null mice. Male Mstn null and wild-type mice of similar genetic backgrounds received either 0 (control) or 20 p.p.m. clenbuterol in tap water free choice for 14 days. Several traits were measured to estimate muscle and fat growth. The Mstn null mutation resulted in increased body and empty carcass weight, increased muscle weights and decreased fat pad weights. Fat content was reduced and protein content was increased in the empty carcasses of Mstn null mice. Similarly, treatment with clenbuterol resulted in increased body and empty carcass weight, increased muscle weights and reduced fat pad weights. Fat content of empty carcasses and viscera was reduced and protein content of empty carcasses was increased with clenbuterol treatment. A significant interaction of genotype and clenbuterol treatment would indicate an altered responsiveness of Mstn null mice to clenbuterol. However, only the weight of gastrocnemius muscles exhibited a significant (P 5 0.01) interaction of genotype and clenbuterol treatment, indicating that Mstn null mice were less responsive to clenbuterol compared with wild-type mice. Thus, for all other traits, the impact of Mstn null mutation and clenbuterol treatment was completely additive. These data suggest that disruption of Mstn function does not alter the response of mice to b-adrenergic agonists.

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“…Therefore experimentation in space flights is necessary to examine the effects of this multifactorial process even if constrained by the limited number of animals that can be studied and the inability to obtain samples at different time points. The occurrence of generalized skeletal muscle hypertrophy in cattle and mice with inactivating mutations of the myostatin gene (Kambadur et al 1997, Grobet et al 1998, Szabo et al 1998 suggests that myostatin is a determinant of skeletal muscle mass. The increase in myostatin mRNA and protein expression in the muscles of the spaceflight rats in association with the reduction in muscle mass, and the subsequent normalization of both variables upon reacclimatization to ground conditions, is consistent with the hypothesis that myostatin is an inhibitor of skeletal muscle growth in adult animals.…”

Section: Discussionmentioning

confidence: 99%

“…However, we do not know if IGF-II expression in the muscle is affected by spaceflight. Myostatin, a member of the transforming growth factor (TGF)-family of growth factors, has been proposed as an inhibitor of skeletal muscle mass , Szabo et al 1998. Inactivating mutations of the myostatin gene in cattle and mice are associated with generalized increase in skeletal muscle (Kambadur et al 1997, Grobet et al 1998, Szabo et al 1998.…”

Section: Introductionmentioning

confidence: 99%

Myostatin and insulin-like growth factor-I and -II expression in the muscle of rats exposed to the microgravity environment of the NeuroLab space shuttle flight

Lalani

Bhasin²,

Byhower³

et al. 2000

Journal of Endocrinology

156

115

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The mechanism of the loss of skeletal muscle mass that occurs during spaceflight is not well understood. Myostatin has been proposed as a negative modulator of muscle mass, and IGF-I and IGF-II are known positive regulators of muscle differentiation and growth. We investigated whether muscle loss associated with spaceflight is accompanied by increased levels of myostatin and a reduction in IGF-I and -II levels in the muscle, and whether these changes correlate with an increase in muscle proteolysis and apoptosis. Twelve male adult rats sent on the 17-day NASA STS-90 NeuroLab space flight were divided upon return to earth into two groups, and killed either 1 day later (R1) or after 13 days of acclimatization (R13). Ground-based control rats were maintained for the same periods in either vivarium (R3 and R15, respectively), or flight-simulated cages (R5 and R17, respectively). RNA and protein were isolated from the tibialis anterior, biceps femoris, quadriceps, and gastrocnemius muscles. Myostatin, IGF-I, IGF-II and proteasome 2c mRNA concentrations were determined by reverse transcription/PCR; myostatin and ubiquitin mRNA were also measured by Northern blot analysis; myostatin protein was estimated by immunohistochemistry; the apoptotic index and the release of 3-methylhistidine were determined respectively by the TUNEL assay and by HPLC. Muscle weights were 19-24% lower in the R1 rats compared with the control R3 and R5 rats, but were not significantly different after the recovery period. The myostatin/ -actin mRNA ratios (means ...) were higher in the muscles of the R1 rats compared with the control R5 rats: 5·0-fold in tibialis (5·35 1·85 vs 1·07 0·26), 3·0-fold in biceps (2·46 0·70 vs 0·81 0·04), 1·9-fold in quadriceps (7·84 1·73 vs 4·08 0·52), and 2·2-fold in gastrocnemius (0·99 0·35 vs 0·44 0·17). These values also normalized upon acclimatization. Our antibody against a myostatin peptide was validated by detection of the recombinant human myostatin protein on Western blots, which also showed that myostatin immunostaining was increased in muscle sections from R1 rats, compared with control R3 rats, and normalized upon acclimatization. In contrast, IGF-II mRNA concentrations in the muscles from R1 rats were 64-89% lower than those in R3 animals. With the exception of the gastrocnemius, IGF-II was also decreased in R5 animals maintained in flight-simulated cages, and normalized upon acclimatization. The intramuscular IGF-I mRNA levels were not significantly different between the spaceflight rats and the controls. No increase was found in the proteolysis markers 3-methyl histidine, ubiquitin mRNA, and proteasome 2C mRNA. In conclusion, the loss of skeletal muscle mass that occurs during spaceflight is associated with increased myostatin mRNA and protein levels in the skeletal muscle, and a decrease in IGF-II mRNA levels. These alterations are normalized upon restoration of normal gravity and caging conditions. These data suggest that reciprocal changes in the expression of myostatin and IGF-II may co...

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A deletion in the myostatin gene causes the compact ( Cmpt ) hypermuscular mutation in mice

Cited by 144 publications

References 10 publications

Lack of myostatin results in excessive muscle growth but impaired force generation

Lack of myostatin results in excessive muscle growth but impaired force generation

The myostatin null mutation and clenbuterol administration elicit additive effects in mice

Myostatin and insulin-like growth factor-I and -II expression in the muscle of rats exposed to the microgravity environment of the NeuroLab space shuttle flight

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