RESUMO
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. Loss of EWS leads to a significant decrease in mitochondria abundance and activity, which is caused by a rapid degradation of Peroxisome proliferator-activated receptor γ Coactivator (PGC-1α), a central regulator of mitochondria biogenesis, function, and cellular energy metabolism. EWS inactivation leads to increased ubiquitination and proteolysis of PGC-1α via proteasome pathway. Complementation of EWS in Ews-deficient cells restores PGC-1α and mitochondrial abundance. We found that expression of E3 ubiquitin ligase, FBXW7 (F-box/WD40 domain protein 7), is increased in the absence of Ews and depletion of Fbxw7 in Ews-null cells restores PGC-1α expression and mitochondrial density. Consistent with these findings, mitochondrial abundance and activity are significantly reduced in brown fat and skeletal muscles of Ews-deficient mice. Furthermore, expression of mitochondrial biogenesis, respiration and fatty acid ß-oxidation genes is significantly reduced in the liver of Ews-null mice. These results demonstrate a novel role of EWS in mitochondrial and cellular energy homeostasis by controlling PGC-1α protein stability, and further implicate altered mitochondrial and energy metabolism in cancers harboring the EWS translocation.
Assuntos
Mitocôndrias/metabolismo , Proteína EWS de Ligação a RNA/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Tecido Adiposo Marrom/metabolismo , Animais , DNA Mitocondrial/metabolismo , Metabolismo Energético , Proteínas F-Box/metabolismo , Proteína 7 com Repetições F-Box-WD , Ácidos Graxos/química , Ácidos Graxos/metabolismo , Perfilação da Expressão Gênica , Células HEK293 , Homeostase , Humanos , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Eletrônica de Transmissão , Músculo Esquelético/metabolismo , Oxigênio/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Conformação Proteica , Proteína EWS de Ligação a RNA/metabolismo , Ubiquitina/química , Ubiquitina-Proteína Ligases/metabolismoRESUMO
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.
Assuntos
Envelhecimento , Proteínas Morfogenéticas Ósseas/metabolismo , Cardiomegalia/metabolismo , Fatores de Diferenciação de Crescimento/metabolismo , Miócitos Cardíacos/metabolismo , Parabiose , Animais , Feminino , Humanos , MasculinoRESUMO
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. Furthermore, the N-terminal domain of Fst288 undergoes conformational rearrangements to bind myostatin and likely acts as a site of specificity for the antagonist. In addition, a unique continuous electropositive surface is created when myostatin binds Fst288, which significantly increases the affinity for heparin. This translates into stronger interactions with the cell surface and enhanced myostatin degradation in the presence of either Fst288 or Fst315. Overall, we have identified several characteristics unique to myostatin that will be paramount to the rational design of myostatin inhibitors that could be used in the treatment of muscle-wasting disorders.
Assuntos
Folistatina/química , Heparina/metabolismo , Miostatina/química , Ativinas , Sequência de Aminoácidos , Animais , Sítios de Ligação , Células CHO , Cricetinae , Cricetulus , Heparina/química , Modelos Moleculares , Dados de Sequência Molecular , Conformação ProteicaRESUMO
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. We present a 53-year old female with a 10-year history of progressive generalized muscle overgrowth. Congo-red staining and immunohistochemistry revealed perivascular lambda light chain amyloid deposits, apparent only in a second muscle biopsy. The numbers of central nuclei and satellite cells were increased, suggesting enhanced muscle progenitor cell formation. Despite the chronicity of the light chain disease, the patient showed complete resolution of hematologic findings and significant improvement of her muscle symptoms following autologous bone marrow transplantation. This case highlights the importance of early diagnosis and therapy for this treatable cause of a chronic myopathy with muscle hypertrophy.
Assuntos
Amiloidose/imunologia , Cadeias Leves de Imunoglobulina/metabolismo , Doenças Musculares/imunologia , Adulto , Amiloidose/diagnóstico , Amiloidose/terapia , Transplante de Medula Óssea , Feminino , Humanos , Cadeias Leves de Imunoglobulina/sangue , Doenças Musculares/diagnóstico , Doenças Musculares/terapia , Paraproteinemias , Células Satélites de Músculo Esquelético , Transplante AutólogoRESUMO
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. In human skeletal muscle, we observed that markers of oxidative fibers and mitochondria correlated positively with expression levels of PPARGC1A and CDK4 and negatively with expression levels of CDKN2A, a locus significantly associated with type 2 diabetes. Mice expressing a constitutively active Cdk4 that cannot bind its inhibitor p16INK4a, a product of the CDKN2A locus, were protected from obesity and diabetes. Their muscles exhibited increased oxidative fibers, improved mitochondrial properties, and enhanced glucose uptake. In contrast, loss of Cdk4 or skeletal muscle-specific deletion of Cdk4's target, E2F3, depleted oxidative myofibers, deteriorated mitochondrial function, and reduced exercise capacity, while increasing diabetes susceptibility. E2F3 activated the mitochondrial sensor PPARGC1A in a Cdk4-dependent manner. CDK4, E2F3, and PPARGC1A levels correlated positively with exercise and fitness and negatively with adiposity, insulin resistance, and lipid accumulation in human and rodent muscle. All together, these findings provide mechanistic insight into regulation of skeletal muscle fiber-specification that is of relevance to metabolic and muscular diseases.
Assuntos
Diabetes Mellitus Tipo 2 , Doenças Musculares , Camundongos , Animais , Humanos , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares de Contração Lenta/metabolismo , Músculo Esquelético/metabolismo , Doenças Musculares/metabolismo , Obesidade/metabolismo , Estresse Oxidativo , Desenvolvimento Muscular , Fator de Transcrição E2F3/metabolismo , Quinase 4 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/metabolismoRESUMO
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. Conflicting results have been obtained in previous analyses of the role of MSTN on satellite cell quiescence. Here, we inhibited MSTN in adult mice with a soluble activin receptor type IIB and analysed the incorporation of new nuclei using 5-bromo-2-deoxyuridine (BrdU) labelling by isolating individual myofibres. We found that satellite cells are activated by MSTN inhibition. By varying the dose and time course for MSTN inhibition, however, we found that myofibre hypertrophy precedes the incorporation of new nuclei, and that the overall number of new nuclei is relatively low compared to the number of total myonuclei. These results reconcile some of the previous work obtained by other methods. In contrast with previous reports, we also found that Mstn null mice do not have increased satellite cell numbers during adulthood and are not resistant to sarcopaenia. Our results support a previously proposed model of hypertrophy in which hypertrophy can precede satellite cell activation. Studies of the metabolic and functional effects of postnatal MSTN inhibition are needed to determine the consequences of increasing the cytoplasm/myonuclear ratio after MSTN inhibition.
Assuntos
Receptores de Activinas Tipo II/administração & dosagem , Proliferação de Células/efeitos dos fármacos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Miostatina/antagonistas & inibidores , Células Satélites de Músculo Esquelético/efeitos dos fármacos , Fatores Etários , Envelhecimento/metabolismo , Animais , Replicação do DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Hipertrofia , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Miostatina/genética , Miostatina/metabolismo , Proteínas Recombinantes de Fusão/administração & dosagem , Sarcopenia/metabolismo , Sarcopenia/patologia , Células Satélites de Músculo Esquelético/metabolismo , Células Satélites de Músculo Esquelético/patologia , Fatores de TempoRESUMO
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. To analyze the response of Mstn(-/-) muscle to endurance exercise in detail, we carried out endurance training over 4 weeks to examine muscle mass, histology, and oxidative enzyme activity. We found that muscle mass was reduced with training in several muscles from both genotypes, with no evidence of muscle damage. Citrate synthase activity was increased with training in control and mutant mice. Non-trained Mstn(-/-) mice did, however, have lower maximal exercise capacity compared with Mstn(+/+) mice. These results show that Mstn(-/-) muscle retains the metabolic plasticity necessary to adapt normally to endurance training.
Assuntos
Miostatina/genética , Miostatina/fisiologia , Condicionamento Físico Animal/fisiologia , Resistência Física/genética , Resistência Física/fisiologia , Animais , Peso Corporal/genética , Peso Corporal/fisiologia , Citrato (si)-Sintase/metabolismo , Corantes , Azul Evans , Glicólise , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Musculares/metabolismo , Músculo Esquelético/enzimologia , Músculo Esquelético/fisiologia , Tamanho do Órgão/genética , Tamanho do Órgão/fisiologia , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Succinato Desidrogenase/metabolismoRESUMO
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. In order to investigate the possible functional redundancy of myostatin and Gdf11, we analyzed the effect of eliminating the functions of both of these signaling molecules. RESULTS: We show that Mstn-/- Gdf11-/- mice have more extensive homeotic transformations of the axial skeleton than Gdf11-/- mice in addition to skeletal defects not seen in single mutants such as extra forelimbs. We also show that deletion of Gdf11 specifically in skeletal muscle in either Mstn+/+ or Mstn-/- mice does not affect muscle size, fiber number, or fiber type. CONCLUSION: These results provide evidence that myostatin and Gdf11 have redundant functions in regulating skeletal patterning in mice but most likely not in regulating muscle size.
Assuntos
Desenvolvimento Ósseo , Proteínas Morfogenéticas Ósseas/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Fatores de Diferenciação de Crescimento/metabolismo , Músculo Esquelético/embriologia , Miostatina/metabolismo , Animais , Proteínas Morfogenéticas Ósseas/genética , Feminino , Fatores de Diferenciação de Crescimento/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miostatina/genéticaRESUMO
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. To investigate whether myostatin might be an effective target for suppressing the development of obesity in settings of abnormal fat accumulation, we analyzed the effect of the Mstn mutation in two genetic models of obesity, agouti lethal yellow (A(y)) and obese (Lep(ob/ob)). In each case, loss of Mstn led to a partial suppression of fat accumulation and of abnormal glucose metabolism. Our findings raise the possibility that pharmacological agents that block myostatin function may be useful not only for enhancing muscle growth, but also for slowing or preventing the development of obesity and type 2 diabetes.
Assuntos
Tecido Adiposo/patologia , Fator de Crescimento Transformador beta/deficiência , Animais , Diabetes Mellitus Tipo 2/prevenção & controle , Ingestão de Alimentos , Feminino , Glucose/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , Miostatina , Obesidade/prevenção & controle , Tamanho do Órgão , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/fisiologiaRESUMO
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. However, even obese animals have an increase in energy expenditure compared to normal weight animals suggesting this is an incomplete explanation. We have previously developed a computational model to estimate energy output, fat oxidation and respiratory quotient from food intake and body composition measurements to more accurately account for changes in body composition in rodents over time. Here we use this approach to understand the dynamic changes in energy output, intake, fat oxidation and respiratory quotient in muscular mice carrying a dominant negative activin receptor IIB expressed specifically in muscle. We found that muscular mice had higher food intake and higher energy output when fed either chow or a high-fat diet for 15 weeks compared to WT mice. Transgenic mice also matched their rate of fat oxidation to the rate of fat consumed better than WT mice. Surprisingly, when given a choice between high-fat diet and Ensure® drink, transgenic mice consumed relatively more calories from Ensure® than from the high-fat diet despite similar caloric intake to WT mice. When switching back and forth between diets, transgenic mice adjusted their intake more rapidly than WT to restore normal caloric intake. Our results show that mice with myostatin inhibition in muscle are better at adjusting energy intake and output on diets of different macronutrient composition than WT mice to maintain energy balance and resist weight gain.
Assuntos
Metabolismo Energético/fisiologia , Hipertrofia/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Doenças Musculares/metabolismo , Animais , Composição Corporal/fisiologia , Dieta Hiperlipídica , Ingestão de Alimentos/fisiologia , Masculino , Camundongos , Estudos Prospectivos , Estudos RetrospectivosRESUMO
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. We asked whether MSTN inhibition would increase muscle mass and decrease hyperglycemia in mice treated with streptozotocin (STZ) to destroy pancreatic beta cells. After diabetes developed, mice were treated with a soluble MSTN/activin receptor fused to Fc (ACVR2B:Fc). ACVR2B:Fc increased body weight and muscle mass compared to vehicle treated mice. Unexpectedly, ACVR2B:Fc reproducibly exacerbated hyperglycemia within approximately one week of administration. ACVR2B:Fc treatment also elevated serum levels of the glucocorticoid corticosterone. These results suggest that although MSTN/activin inhibitors increased muscle mass, they may be counterproductive in improving health in patients with T1DM.
Assuntos
Receptores de Activinas Tipo II/metabolismo , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/tratamento farmacológico , Miostatina/metabolismo , Proteínas Recombinantes/uso terapêutico , Estreptozocina/farmacologia , Estreptozocina/uso terapêutico , Receptores de Activinas Tipo II/genética , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Doenças Musculares , Miostatina/genética , Proteínas Recombinantes/farmacologiaRESUMO
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. In a recent study, we showed that increasing skeletal muscle mass by inhibiting signaling of myostatin, a transforming growth factor ß (TGFß) family member that negatively regulates muscle growth, prevents the development of diabetes in a mouse model of lipodystrophy. Muscle-specific myostatin inhibition also prevented hyperphagia suggesting muscle may regulate food intake. Here we discuss these results in the context of strategies to increase muscle insulin sensitivity as well as new findings about the effects of myostatin and other TGFß family members on similar metabolic processes.
RESUMO
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. Although erythropoietin receptor is expressed on muscle progenitor/precursor cells and is down regulated in mature muscle fibers, we found that skeletal muscles from mice with high erythropoietin production in vivo exhibit an increase in the proportion of slow twitch myofibers and increased mitochondrial activity. In comparison, skeletal muscle from wild type mice and mice with erythropoietin activity restricted to erythroid tissue have fewer slow twitch myofibers and reduced mitochondrial activity. PGC-1α activates mitochondrial oxidative metabolism and converts the fast myofibers to slow myofibers when overexpressed in skeletal muscle and PGC-1α was elevated by 2-fold in mice with high erythropoietin. In vitro erythropoietin treatment of primary skeletal myoblasts increased mitochondrial biogenesis gene expression including PGC-1α by 2.6-fold, CytC by 2-fold, oxygen consumption rate by 2-fold, and citrate synthase activity by 58%. Erythropoietin also increases AMPK, which induces PGC-1α and stimulates slow oxidative fiber formation. These data suggest that erythropoietin contributes to skeletal muscle fiber programming and metabolism, and increases PGC-1α and AMPK activity during muscle development directly to affect the proportion of slow/fast twitch myofibers in mature skeletal muscle.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Eritropoetina/metabolismo , Fibras Musculares de Contração Rápida/metabolismo , Fibras Musculares de Contração Lenta/metabolismo , Fatores de Transcrição/metabolismo , Animais , Células Cultivadas , Citrato (si)-Sintase/metabolismo , Eritropoese , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mitocôndrias/metabolismo , Contração Muscular/fisiologia , Mioblastos , Oxirredução , Consumo de Oxigênio , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Receptores da Eritropoetina/biossíntese , Receptores da Eritropoetina/metabolismo , Transdução de SinaisRESUMO
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. To test this hypothesis, we inhibited MSTN signaling in a diabetic model of generalized lipodystrophy to analyze its effects on glucose metabolism separate from effects on adipose mass. A-ZIP/F1 lipodystrophic mice were crossed to mice expressing a dominant-negative MSTN receptor (activin receptor type IIB) in muscle. MSTN inhibition in A-ZIP/F1 mice reduced blood glucose, serum insulin, triglyceride levels, and the rate of triglyceride synthesis, and improved insulin sensitivity. Unexpectedly, hyperphagia was normalized by MSTN inhibition in muscle. Blood glucose and hyperphagia were reduced in double mutants independent of the adipokine leptin. These results show that the effect of MSTN inhibition on insulin sensitivity is not secondary to an effect on adipose mass and that MSTN inhibition may be an effective treatment for diabetes. These results further suggest that muscle may play a heretofore unappreciated role in regulating food intake.
Assuntos
Diabetes Mellitus/genética , Hiperfagia/genética , Resistência à Insulina/genética , Lipodistrofia/complicações , Músculo Esquelético/metabolismo , Miostatina/genética , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Glicemia/metabolismo , Diabetes Mellitus/etiologia , Diabetes Mellitus/metabolismo , Modelos Animais de Doenças , Glucose/farmacologia , Hiperfagia/etiologia , Hiperfagia/metabolismo , Insulina/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/genética , Lipodistrofia/genética , Lipodistrofia/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Músculo Esquelético/efeitos dos fármacos , Miostatina/metabolismoRESUMO
Myostatin is a member of the transforming growth factor-ß/bone morphogenetic protein (TGF-ß/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. In addition, recent work has explored the role of myostatin in substrate mobilization, uptake, and/or utilization of muscle independent of its effects on body composition. Finally, the effects of both endurance and resistance exercise on myostatin expression, as well as the potential role of myostatin in the beneficial metabolic adaptations occurring in response to exercise, have also begun to be delineated in greater detail. The purpose of this review was to summarize the work to date on the expression and function of myostatin in obesity, diabetes, and exercise adaptation.
Assuntos
Adaptação Fisiológica , Diabetes Mellitus Tipo 2/fisiopatologia , Exercício Físico/fisiologia , Miostatina/biossíntese , Miostatina/fisiologia , Obesidade/fisiopatologia , Tecido Adiposo/fisiologia , Animais , Feminino , Humanos , Fígado/fisiologia , Masculino , Camundongos , Músculo Esquelético/fisiologia , RatosRESUMO
Myostatin is a member of the transforming growth factor ß 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. In this review I will describe the present state of our understanding of the role of myostatin and the closely related growth factor growth/differentiation factor 11 on metabolism.
RESUMO
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. This is associated with a reduction in the expression of PGC1alpha and COX IV, proteins which play important roles in maintaining mitochondrial function. Furthermore, we show that these changes in signalling and protein expression are largely independent of alterations in intramuscular amino acid content. Our findings, therefore, reveal potential new mechanisms and further contribute to our understanding of myostatin-regulated skeletal muscle growth and function.
Assuntos
Desenvolvimento Muscular/genética , Músculo Esquelético/metabolismo , Transdução de Sinais/genética , Sirolimo/metabolismo , Animais , Hipertrofia/metabolismo , Mamíferos/genética , Mamíferos/metabolismo , Camundongos , Miostatina , Biossíntese de Proteínas , Proteínas/genética , Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
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. Despite reduced lipid oxidation in skeletal muscle, Mstn(-/-) mice had no change in the rate of whole body lipid oxidation. In contrast, Mstn(-/-) mice had increased glucose utilization and insulin sensitivity as measured by indirect calorimetry, glucose and insulin tolerance tests, and hyperinsulinemic-euglycemic clamp. To determine whether these metabolic effects were due primarily to the loss of myostatin signaling in muscle or adipose tissue, we compared two transgenic mouse lines carrying a dominant negative activin IIB receptor expressed specifically in adipocytes or skeletal muscle. We found that inhibition of myostatin signaling in adipose tissue had no effect on body composition, weight gain, or glucose and insulin tolerance in mice fed a standard diet or a high-fat diet. In contrast, inhibition of myostatin signaling in skeletal muscle, like Mstn deletion, resulted in increased lean mass, decreased fat mass, improved glucose metabolism on standard and high-fat diets, and resistance to diet-induced obesity. Our results demonstrate that Mstn(-/-) mice have an increase in insulin sensitivity and glucose uptake, and that the reduction in adipose tissue mass in Mstn(-/-) mice is an indirect result of metabolic changes in skeletal muscle. These data suggest that increasing muscle mass by administration of myostatin antagonists may be a promising therapeutic target for treating patients with obesity or diabetes.
Assuntos
Tecido Adiposo/metabolismo , Resistência à Insulina/fisiologia , Insulina/metabolismo , Músculo Esquelético/metabolismo , Miostatina/antagonistas & inibidores , Animais , Dieta , Gorduras na Dieta , Glucose/metabolismo , Técnica Clamp de Glucose , Humanos , Metabolismo dos Lipídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Esquelético/anatomia & histologia , Miostatina/metabolismo , Oxirredução , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/fisiologiaRESUMO
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. Diaphragm muscle showed less fibrosis and fatty remodeling, suggesting improved muscle regeneration.
Assuntos
Distrofias Musculares/genética , Distrofias Musculares/patologia , Fator de Crescimento Transformador beta/deficiência , Fator de Crescimento Transformador beta/genética , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Camundongos Mutantes , Fibras Musculares Esqueléticas/patologia , Distrofias Musculares/fisiopatologia , Miostatina , Índice de Gravidade de DoençaRESUMO
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. Here, we show that members of the bone morphogenetic protein-1/tolloid (BMP-1/TLD) family of metalloproteinases can cleave the myostatin propeptide in this complex and can thereby activate latent myostatin. Furthermore, we show that a mutant form of the propeptide resistant to cleavage by BMP-1/TLD proteinases can cause significant increases in muscle mass when injected into adult mice. These findings raise the possibility that members of the BMP-1/TLD family may be involved in activating latent myostatin in vivo and that molecules capable of inhibiting these proteinases may be effective agents for increasing muscle mass for both human therapeutic and agricultural applications.