[Show abstract][Hide abstract] ABSTRACT: Confusing results have been reported regarding the influence of nutritional status on myostatin levels. Some studies indicate that short-term fasting results in increased myostatin mRNA levels in skeletal muscle, evident in several species. In contrast, other studies have demonstrated either a decrease or no change in myostatin levels during fasting. In the present study, we investigated the effect of different patterns of food deprivation on muscle myostatin expression in both newborn and adult rats. Adjustment of litter size in neonatal rats is a well-established model to study the effect of early overfeeding or underfeeding on body composition and in this study resulted in modifications in the pattern of muscle myostatin expression. Rat pups growing in large litters (22-24 newborns) showed a decrease in muscle myostatin mRNA and protein levels at 24 days of age. Interestingly, these effects were maintained at 60 days of age despite rats having free access to food since weaning, thus suggesting that changes in myostatin expression induced by neonatal reduction of food intake are long-lasting. In contrast, no changes in myostatin mRNA levels were observed in adult rats when food intake was decreased during 7 days by either food restriction or central leptin treatment. Similar results were obtained when food restriction was maintained in adult rats for a longer period (7 weeks), despite significant muscle loss. Overall, these data suggest that myostatin gene expression is programmed by nutritional status in neonatal life.
Journal of physiology and biochemistry 03/2013; 69(1):15-23. DOI:10.1007/s13105-012-0183-x · 1.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Besides its key role in the regulation of muscle growth during development, myostatin also appears to be involved in muscle homeostasis in adults, and its expression is upregulated during muscle atrophy. Since muscle physiology is greatly influenced by thyroid status, and the myostatin promoter region contains several putative thyroid hormone response elements, in the present study we examined the possible role of thyroid hormones in the regulation of myostatin gene expression. Adult male rats were made either hypothyroid or hyperthyroid by means of administration of 0.1% amino- triazole (AMT) in drinking water for 4 weeks, or daily injections of Levo-T4 (L-T4) (100 microg/rat) for 3 weeks, respectively. At the end of the treatment period, both myostatin mRNA and protein content were increased in AMT-treated rats in relation to control rats. In contrast, no changes in myostatin mRNA levels were detected in L-T4-treated rats. The role of thyroid hormones in the regulation of myostatin expression was also investigated in C2C12 cells in vitro. Treatment of C2C12 cells with thyroid hormones stimulated their differentiation into multinucleated myotubes, but did not induce any change in myostatin mRNA abundance. In all, our findings demonstrate that myostatin expression is increased in hypothyroid rats, thus supporting a possible role for this factor in the pathogenesis of the muscle loss that may occur in hypothyroidism.
[Show abstract][Hide abstract] ABSTRACT: The demonstration that myostatin may negatively regulate muscle mass in adult individuals has raised the possibility of targeting the myostatin pathway to increase muscle growth in a variety of muscle-degenerative and -wasting conditions. To gain further insight into the possible role of myostatin in primary muscle diseases, the authors investigated the expression of muscle myostatin in children with congenital fiber type 1 disproportion, in others with neurogenic muscular atrophy, in others with myotonia congenita, in others with infantile glycogenosis type II, in others with Prader-Willi syndrome, and in 4 age-matched controls. No differences in the pattern of myostatin expression were found in any case, even in those patients with prominent muscular atrophy or hypertrophy. These findings suggest that muscle alterations that can be observed in primary muscle diseases do not depend on changes in myostatin expression.
[Show abstract][Hide abstract] ABSTRACT: The demonstration that myostatin may negatively regulate muscle mass in adult individuals has raised the possibility of targeting the myostatin pathway in order to increase muscle growth in a variety of muscle degenerative and wasting conditions. In this regard, blockade of endogenous myostatin results in anatomic, biochemical, and physiologic improvement in the dystrophic phenotype in the mdx mouse. Moreover, myostatin messenger ribonucleic acid levels are decreased in the regenerated muscle of these mice, suggesting that myostatin may also be involved in the pathogenesis of the disease. To gain further insight into the possible role of myostatin in muscle degenerative diseases, the present work investigates the expression of muscle myostatin in children with muscular dystrophies and mitochondrial encephalomyopathies. No differences in the pattern of myostatin expression were evident in any case, even in those patients with prominent muscular atrophy. These findings suggest that muscle loss that can be observed in muscle degenerative diseases does not depend on changes in myostatin expression.
[Show abstract][Hide abstract] ABSTRACT: Myostatin is a protein belonging to the transforming growth factor (TGF)-β family, which plays a major role in controlling muscular development. As occurs with other members of the TGF-β family, myostatin is synthesised as an inactive precursor that needs to undergo proteolytic processing to give rise to the mature peptide. Myostatin is almost exclusively expressed in skeletal muscle, where it acts in an autocrine/paracrine fashion to inhibit muscle growth. In mice, myostatin blockade results in a dramatic increase in muscle mass and decreased adiposity. The effect on adipose tissue is so marked that myostatin blockade is even capable of reverting obesity in several strains of obese mice. Because of these actions, the use of myostatin-blocking agents has been proposed as a new strategy in the prevention or treatment of obesity and type 2 diabetes, as well as in diseases in which muscular anabolism needs to be stimulated (such as some muscular dystrophies and wasting conditions).
Endocrinología y Nutrición 09/2005; 52(7). DOI:10.1016/S1575-0922(05)71031-7
[Show abstract][Hide abstract] ABSTRACT: Myostatin is a member of the TGF-beta superfamily that is essential for proper regulation of skeletal muscle growth. As do other TGF-beta superfamily members, myostatin signals into the cell via a receptor complex that consists of two distinct transmembrane proteins, known as the type I and type II receptors. Vertebrates have seven distinct type I receptors, each of which can mix and match with one of five type I receptors to mediate signals for all the TGF-beta family ligands. Accumulating evidence indicates that myostatin shares its pair of receptors with activin, and therefore, the question arises about how specificity in signaling is achieved. Our hypothesis is that a mechanism has to exist to restrict myostatin actions to the muscle cells. To investigate this possibility, we compared the effect of endogenous myostatin (myostatin overexpressed by myoblasts) and exogenous myostatin (recombinant myostatin added to the culture medium) in cultured myoblasts. As opposed to exogenous myostatin, endogenous myostatin induced the transcription of a reporter vector in cultured myoblasts. Notably, the myostatin concentrations that failed to induce a response in myoblasts were effective in MCF-7 cells (human mammary carcinoma) and in HepG2 cells (human hepatic carcinoma). Based on our observations, we propose that a mechanism exists that differentially regulates the bioavailability of endogenous and exogenous myostatin to muscle cells. This is consistent with a model in which myostatin actions are exerted in vivo in an autocrine fashion.
[Show abstract][Hide abstract] ABSTRACT: Myostatin (MSTN), a transforming growth factor (TGF)-beta superfamily member, has been shown to negatively regulate muscle growth by inhibiting muscle precursor cell proliferation. Here, we stably transfected C(2)C(12) cells with mouse MSTN cDNA to investigate its possible role in myoblast differentiation. We found that MSTN cDNA overexpression reversibly inhibits the myogenic process by downregulating mRNA levels of the muscle regulatory factors myoD and myogenin, as well as the activity of their downstream target creatine kinase. Taking into consideration that MSTN expression during development is restricted to muscle, our results suggest that MSTN probably regulates myogenic differentiation by an autocrine mechanism.
[Show abstract][Hide abstract] ABSTRACT: During the myogenic process in vitro, proliferating myoblasts withdraw irreversible from the cell cycle, acquire an apoptosis-resistant phenotype, and fuse into mature myotubes. The key factor regulating both myocyte cell cycle exit and viability during this transition is the the cyclin-dependent kinase inhibitor p21(cip1). Here we show that the expression of myostatin, a TGF-beta superfamily member known to act as a negative regulator of muscle growth, is upregulated in the course of C2C12 cells myogenesis. We also show that transient transfection of C2C12 myobasts with an expression vector encoding mouse myostatin cDNA efficiently inhibits cell proliferation. Paradoxically, myostatin cDNA overexpression also enhances the survival of differentiating C2C12 myocytes, probably by a mechanism involving, at least in part, upregulation of p21(cip1) mRNA. Our results suggest that myostatin role in myogenesis is more complex than initially suggested and involves another level of regulation apart from inhibition of myoblast proliferation.
Biochemical and Biophysical Research Communications 02/2001; 280(2):561-6. DOI:10.1006/bbrc.2000.4159 · 2.30 Impact Factor