CDK4-E2F3 signals enhance oxidative skeletal muscle fiber numbers and function to affect myogenesis and metabolism.

Understanding how skeletal muscle fiber proportions are regulated is vital to understanding muscle function. Oxidative and glycolytic skeletal muscle fibers differ in their contractile ability, mitochondrial activity, and metabolic properties. Fiber-type proportions vary in normal physiology and disease states, although the underlying mechanisms are unclear.

Modeling Energy Dynamics in Mice with Skeletal Muscle Hypertrophy Fed High Calorie Diets.

Retrospective and prospective studies show that lean mass or strength is positively associated with metabolic health. Mice deficient in myostatin, a growth factor that negatively regulates skeletal muscle mass, have increased muscle and body weights and are resistant to diet-induced obesity. Their leanness is often attributed to higher energy expenditure in the face of normal food intake.

Inactivation of EWS reduces PGC-1α protein stability and mitochondrial homeostasis.

EWS (Ewing sarcoma) encodes an RNA/ssDNA binding protein that is frequently rearranged in a number of different cancers by chromosomal translocations. Physiologically, EWS has diverse and essential roles in various organ development and cellular processes. In this study, we uncovered a new role of EWS in mitochondrial homeostasis and energy metabolism.

A soluble activin receptor type IIB does not improve blood glucose in streptozotocin-treated mice.

Type 1 diabetes mellitus (T1DM), or insulin dependent DM, is accompanied by decreased muscle mass. The growth factor myostatin (MSTN) is a negative regulator of muscle growth, and a loss of MSTN signaling has been shown to increase muscle mass and prevent the development of obesity, insulin resistance and lipodystrophic diabetes in mice. The effects of MSTN inhibition in a T1DM model on muscle mass and blood glucose are unknown.

Through thick and thin: a circulating growth factor inhibits age-related cardiac hypertrophy.

In an intriguing new study, Loffredo et al report that joining the circulation of old mice with that of young mice reduces age-related cardiac hypertrophy. They also found that the growth factor growth/differentiation factor 11 is a circulating negative regulator of cardiac hypertrophy which suggests that raising growth/differentiation factor 11 levels may be useful to treat cardiac hypertrophy associated with aging.

Increasing muscle mass to improve metabolism.

Skeletal muscle insulin resistance is a predictor of the development of type 2 diabetes and maintenance of adequate muscle glucose disposal in muscle may help to prevent diabetes. Lipodystrophy is a type of diabetes caused by a reduction of white adipose tissue and the adipokine leptin. Lipidemia, insulin resistance and hyperphagia develop as a consequence.

Erythropoietin contributes to slow oxidative muscle fiber specification via PGC-1α and AMPK activation.

Erythropoietin activity, required for erythropoiesis, is not restricted to the erythroid lineage. In light of reports on the metabolic effects of erythropoietin, we examined the effect of erythropoietin signaling on skeletal muscle fiber type development. Skeletal muscles that are rich in slow twitch fibers are associated with increased mitochondrial oxidative activity and corresponding expression of related genes compared to muscle rich in fast twitch fibers.

Chronic myopathy due to immunoglobulin light chain amyloidosis.

Amyloid myopathy associated with a plasma cell dyscrasia is a rare cause of muscle hypertrophy. It can be a challenging diagnosis, since pathological findings are often elusive. In addition, the mechanism by which immunoglobulin light-chain deposition stimulates muscle overgrowth remains poorly understood.

Myostatin inhibition prevents diabetes and hyperphagia in a mouse model of lipodystrophy.

Lipodystrophies are characterized by a loss of white adipose tissue, which causes ectopic lipid deposition, peripheral insulin resistance, reduced adipokine levels, and increased food intake (hyperphagia). The growth factor myostatin (MSTN) negatively regulates skeletal muscle growth, and mice with MSTN inhibition have reduced adiposity and improved insulin sensitivity. MSTN inhibition may therefore be efficacious in ameliorating diabetes.

Myostatin inhibition induces muscle fibre hypertrophy prior to satellite cell activation.

Muscle fibres are multinucleated post-mitotic cells that can change dramatically in size during adulthood. It has been debated whether muscle fibre hypertrophy requires activation and fusion of muscle stem cells, the satellite cells. Myostatin (MSTN) is a negative regulator of skeletal muscle growth during development and in the adult, and MSTN inhibition is therefore a potential therapy for muscle wasting diseases, some of which are associated with a depletion of satellite cells.

Expression and function of myostatin in obesity, diabetes, and exercise adaptation.

Myostatin is a member of the transforming growth factor-β/bone morphogenetic protein (TGF-β/BMP) superfamily of secreted factors that functions as a potent inhibitor of skeletal muscle growth. Moreover, considerable evidence has accumulated that myostatin also regulates metabolism and that its inhibition can significantly attenuate the progression of obesity and diabetes. Although at least part of these effects on metabolism can be attributable to myostatin's influence over skeletal muscle growth and therefore on the total volume of metabolically active lean body mass, there is mounting evidence that myostatin affects the growth and metabolic state of other tissues, including the adipose and the liver.

METABOLIC FUNCTIONS OF MYOSTATIN AND GDF11.

Myostatin is a member of the transforming growth factor β superfamily of secreted growth factors that negatively regulates skeletal muscle size. Mice null for the myostatin gene have a dramatically increased mass of individual muscles, reduced adiposity, increased insulin sensitivity, and resistance to obesity. Myostatin inhibition in adult mice also increases muscle mass which raises the possibility that anti-myostatin therapy could be a useful approach for treating diseases such as obesity or diabetes in addition to muscle wasting diseases.

Endurance exercise training in myostatin null mice.

The growth factor myostatin (Mstn) is a negative regulator of skeletal muscle mass. Mstn(-/-) muscles are hypertrophied, stronger, and more glycolytic than Mstn(+/+) muscles, suggesting that they might not perform endurance exercise as well as Mstn(+/+) mice. Indeed, it has previously been shown that treadmill exercise training reduces triceps weight in Mstn(-/-) mice.

Mechanisms involved in the enhancement of mammalian target of rapamycin signalling and hypertrophy in skeletal muscle of myostatin-deficient mice.

Myostatin deficiency leads to both an increased rate of protein synthesis and skeletal muscle hypertrophy. However, the mechanisms involved in mediating these effects are not yet fully understood. Here, we demonstrate that genetic loss of myostatin leads to enhanced muscle expression of both protein kinase B and mammalian target of rapamycin/S6K signalling components, consistent with their elevated activity.

The structure of myostatin:follistatin 288: insights into receptor utilization and heparin binding.

Myostatin is a member of the transforming growth factor-beta (TGF-beta) family and a strong negative regulator of muscle growth. Here, we present the crystal structure of myostatin in complex with the antagonist follistatin 288 (Fst288). We find that the prehelix region of myostatin very closely resembles that of TGF-beta class members and that this region alone can be swapped into activin A to confer signalling through the non-canonical type I receptor Alk5.

Redundancy of myostatin and growth/differentiation factor 11 function.

Background: Myostatin (Mstn) and growth/differentiation factor 11 (Gdf11) are highly related transforming growth factor beta (TGFbeta) family members that play important roles in regulating embryonic development and adult tissue homeostasis. Despite their high degree of sequence identity, targeted mutations in these genes result in non-overlapping phenotypes affecting distinct biological processes. Loss of Mstn in mice causes a doubling of skeletal muscle mass while loss of Gdf11 in mice causes dramatic anterior homeotic transformations of the axial skeleton, kidney agenesis, and an increase in progenitor cell number in several tissues.

Myostatin inhibition in muscle, but not adipose tissue, decreases fat mass and improves insulin sensitivity.

Myostatin (Mstn) is a secreted growth factor expressed in skeletal muscle and adipose tissue that negatively regulates skeletal muscle mass. Mstn(-/-) mice have a dramatic increase in muscle mass, reduction in fat mass, and resistance to diet-induced and genetic obesity. To determine how Mstn deletion causes reduced adiposity and resistance to obesity, we analyzed substrate utilization and insulin sensitivity in Mstn(-/-) mice fed a standard chow.

Activation of latent myostatin by the BMP-1/tolloid family of metalloproteinases.

Myostatin is a transforming growth factor beta family member that acts as a negative regulator of skeletal muscle growth. Myostatin circulates in the blood of adult mice in a noncovalently held complex with other proteins, including its propeptide, which maintain the C-terminal dimer in a latent, inactive state. This latent form of myostatin can be activated in vitro by treatment with acid; however, the mechanisms by which latent myostatin is activated in vivo are unknown.

Loss of myostatin attenuates severity of muscular dystrophy in mdx mice.

Myostatin, a transforming growth factor-beta family member, is a negative regulator of skeletal muscle growth. To explore the therapeutic potential of targeting myostatin in settings of muscle degeneration, we crossed myostatin null mutant mice with mdx mice, a model for Duchenne and Becker muscular dystrophy. Mdx mice lacking myostatin were stronger and more muscular than their mdx counterparts.

Induction of cachexia in mice by systemically administered myostatin.

Mice and cattle with genetic deficiencies in myostatin exhibit dramatic increases in skeletal muscle mass, suggesting that myostatin normally suppresses muscle growth. Whether this increased muscling results from prenatal or postnatal lack of myostatin activity is unknown. Here we show that myostatin circulates in the blood of adult mice in a latent form that can be activated by acid treatment.

Suppression of body fat accumulation in myostatin-deficient mice.

Myostatin is a TGF-beta family member that acts as a negative regulator of muscle growth. Mice lacking the myostatin gene (Mstn) have a widespread increase in skeletal muscle mass resulting from a combination of muscle fiber hypertrophy and hyperplasia. Here we show that Mstn-null mice have a significant reduction in fat accumulation with increasing age compared with wild-type littermates, even in the setting of normal food intake (relative to body weight), normal body temperature, and a slightly decreased resting metabolic rate.