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1.
Am J Pathol ; 194(2): 264-279, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37981219

RESUMO

Dystrophin deficiency alters the sarcolemma structure, leading to muscle dystrophy, muscle disuse, and ultimately death. Beyond limb muscle deficits, patients with Duchenne muscular dystrophy have numerous transit disorders. Many studies have highlighted the strong relationship between gut microbiota and skeletal muscle. The aims of this study were: i) to characterize the gut microbiota composition over time up to 1 year in dystrophin-deficient mdx mice, and ii) to analyze the intestine structure and function and expression of genes linked to bacterial-derived metabolites in ileum, blood, and skeletal muscles to study interorgan interactions. Mdx mice displayed a significant reduction in the overall number of different operational taxonomic units and their abundance (α-diversity). Mdx genotype predicted 20% of ß-diversity divergence, with a large taxonomic modification of Actinobacteria, Proteobacteria, Tenericutes, and Deferribacteres phyla and the included genera. Interestingly, mdx intestinal motility and gene expressions of tight junction and Ffar2 receptor were down-regulated in the ileum. Concomitantly, circulating inflammatory markers related to gut microbiota (tumor necrosis factor, IL-6, monocyte chemoattractant protein-1) and muscle inflammation Tlr4/Myd88 pathway (Toll-like receptor 4, which recognizes pathogen-associated molecular patterns) were up-regulated. Finally, in mdx mice, adiponectin was reduced in blood and its receptor modulated in muscles. This study highlights a specific gut microbiota composition and highlights interorgan interactions in mdx physiopathology with gut microbiota as the potential central metabolic organ.


Assuntos
Distrofina , Microbioma Gastrointestinal , Distrofia Muscular de Duchenne , Animais , Humanos , Camundongos , Distrofina/deficiência , Distrofina/genética , Camundongos Endogâmicos mdx , Músculo Esquelético/metabolismo , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/patologia
2.
Int J Mol Sci ; 21(19)2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-33003470

RESUMO

Skeletal muscle has a remarkable plasticity, and its phenotype is strongly influenced by hormones, transcription factors, and physical activity. However, whether skeletal phenotype can be oriented or not during early embryonic stages has never been investigated. Here, we report that pyruvate as the only source of carbohydrate in the culture medium of mouse one cell stage embryo influenced the establishment of the muscular phenotype in adulthood. We found that pyruvate alone induced changes in the contractile phenotype of the skeletal muscle in a sexually dependent manner. For male mice, a switch to a more glycolytic phenotype was recorded, whereas, in females, the pyruvate induced a switch to a more oxidative phenotype. In addition, the influence of pyruvate on the contractile phenotypes was confirmed in two mouse models of muscle hypertrophy: the well-known myostatin deficient mouse (Mstn-/-) and a mouse carrying a specific deletion of p43, a mitochondrial triiodothyronine receptor. Finally, to understand the link between these adult phenotypes and the early embryonic period, we assessed the levels of two histone H3 post-translational modifications in presence of pyruvate alone just after the wave of chromatin reprogramming specific of the first cell cycle. We showed that H3K4 acetylation level was decreased in Mstn-/- 2-cell embryos, whereas no difference was found for H3K27 trimethylation level, whatever the genotype. These findings demonstrate for the first time that changes in the access of energy substrate during the very first embryonic stage can induce a precocious orientation of skeletal muscle phenotype in adulthood.


Assuntos
Citocinas/genética , Hipertrofia/genética , Músculo Esquelético/metabolismo , Miostatina/genética , Acetilação , Animais , Metabolismo dos Carboidratos/genética , Modelos Animais de Doenças , Embrião de Mamíferos , Desenvolvimento Embrionário/genética , Feminino , Genótipo , Glicólise/genética , Hipertrofia/metabolismo , Hipertrofia/patologia , Masculino , Camundongos , Mitocôndrias/metabolismo , Contração Muscular/genética , Músculo Esquelético/patologia , Oxirredução , Fenótipo , Ácido Pirúvico/metabolismo
3.
Am J Physiol Endocrinol Metab ; 317(1): E158-E171, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31039010

RESUMO

Gut microbiota is involved in the development of several chronic diseases, including diabetes, obesity, and cancer, through its interactions with the host organs. It has been suggested that the cross talk between gut microbiota and skeletal muscle plays a role in different pathological conditions, such as intestinal chronic inflammation and cachexia. However, it remains unclear whether gut microbiota directly influences skeletal muscle function. In this work, we studied the impact of gut microbiota modulation on mice skeletal muscle function and investigated the underlying mechanisms. We determined the consequences of gut microbiota depletion after treatment with a mixture of a broad spectrum of antibiotics for 21 days and after 10 days of natural reseeding. We found that, in gut microbiota-depleted mice, running endurance was decreased, as well as the extensor digitorum longus muscle fatigue index in an ex vivo contractile test. Importantly, the muscle endurance capacity was efficiently normalized by natural reseeding. These endurance changes were not related to variation in muscle mass, fiber typology, or mitochondrial function. However, several pertinent glucose metabolism markers, such as ileum gene expression of short fatty acid chain and glucose transporters G protein-coupled receptor 41 and sodium-glucose cotransporter 1 and muscle glycogen level, paralleled the muscle endurance changes observed after treatment with antibiotics for 21 days and reseeding. Because glycogen is a key energetic substrate for prolonged exercise, modulating its muscle availability via gut microbiota represents one potent mechanism that can contribute to the gut microbiota-skeletal muscle axis. Taken together, our results strongly support the hypothesis that gut bacteria are required for host optimal skeletal muscle function.


Assuntos
Metabolismo Energético/fisiologia , Microbioma Gastrointestinal/fisiologia , Glucose/metabolismo , Músculo Esquelético/fisiologia , Animais , Antibacterianos/farmacologia , Disbiose/induzido quimicamente , Disbiose/metabolismo , Disbiose/microbiologia , Disbiose/fisiopatologia , Metabolismo Energético/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Glicogênio/metabolismo , Homeostase/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Músculo Esquelético/efeitos dos fármacos
4.
Biochem Biophys Res Commun ; 516(1): 89-95, 2019 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-31200956

RESUMO

Myostatin (Mstn) inactivation or inhibition is considered as a promising treatment for various muscle-wasting disorders because it promotes muscle growth. However, myostatin-deficient hypertrophic muscles show strong fatigability associated with abnormal mitochondria and lipid metabolism. Here, we investigated whether endurance training could improve lipid metabolism and mitochondrial membrane lipid composition in mice where the Mstn gene was genetically ablated (Mstn-/- mice). In Mstn-/- mice, 4 weeks of daily running exercise sessions (65-70% of the maximal aerobic speed for 1 h) improved significantly aerobic performance, particularly the endurance capacity (up to +280% compared with untrained Mstn-/- mice), to levels comparable to those of trained wild type (WT) littermates. The expression of oxidative and lipid metabolism markers also was increased, as indicated by the upregulation of the Cpt1, Ppar-δ and Fasn genes. Moreover, endurance training also increased, but far less than WT, citrate synthase level and mitochondrial protein content. Interestingly endurance training normalized the cardiolipin fraction in the mitochondrial membrane of Mstn-/- muscle compared with WT. These results suggest that the combination of myostatin inhibition and endurance training could increase the muscle mass while preserving the physical performance with specific effects on cardiolipin and lipid-related pathways.


Assuntos
Deleção de Genes , Metabolismo dos Lipídeos , Miostatina/genética , Animais , Lipidômica , Masculino , Camundongos , Camundongos Knockout , Miostatina/metabolismo , Condicionamento Físico Animal , Resistência Física , Corrida
5.
Cell Mol Life Sci ; 74(10): 1923-1936, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28025671

RESUMO

Muscle satellite cells are resistant to cytotoxic agents, and they express several genes that confer resistance to stress, thus allowing efficient dystrophic muscle regeneration after transplantation. However, once they are activated, this capacity to resist to aggressive agents is diminished resulting in massive death of transplanted cells. Although cell immaturity represents a survival advantage, the signalling pathways involved in the control of the immature state remain to be explored. Here, we show that incubation of human myoblasts with retinoic acid impairs skeletal muscle differentiation through activation of the retinoic-acid receptor family of nuclear receptor. Conversely, pharmacologic or genetic inactivation of endogenous retinoic-acid receptors improved myoblast differentiation. Retinoic acid inhibits the expression of early and late muscle differentiation markers and enhances the expression of myogenic specification genes, such as PAX7 and PAX3. These results suggest that the retinoic-acid-signalling pathway might maintain myoblasts in an undifferentiated/immature stage. To determine the relevance of these observations, we characterised the retinoic-acid-signalling pathways in freshly isolated satellite cells in mice and in siMYOD immature human myoblasts. Our analysis reveals that the immature state of muscle progenitors is correlated with high expression of several genes of the retinoic-acid-signalling pathway both in mice and in human. Taken together, our data provide evidences for an important role of the retinoic-acid-signalling pathway in the regulation of the immature state of muscle progenitors.


Assuntos
Diferenciação Celular , Desenvolvimento Muscular , Mioblastos/citologia , Mioblastos/metabolismo , Tretinoína/metabolismo , Adulto , Animais , Células Cultivadas , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Masculino , Camundongos , Proteína MyoD/genética , Proteína MyoD/metabolismo , Interferência de RNA , Receptores do Ácido Retinoico/metabolismo , Transdução de Sinais
6.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1862(10 Pt A): 1044-1055, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28676454

RESUMO

Myostatin (Mstn) deficiency leads to skeletal muscle overgrowth and Mstn inhibition is considered as a promising treatment for muscle-wasting disorders. Mstn gene deletion in mice also causes metabolic changes with decreased mitochondria content, disturbance in mitochondrial respiratory function and increased muscle fatigability. However the impact of MSTN deficiency on these metabolic changes is not fully elucidated. Here, we hypothesized that lack of MSTN will alter skeletal muscle membrane lipid composition in relation with pronounced alterations in muscle function and metabolism. Indeed, phospholipids and in particular cardiolipin mostly present in the inner mitochondrial membrane, play a crucial role in mitochondria function and oxidative phosphorylation process. We observed that Mstn KO muscle had reduced fat membrane transporter levels (FAT/CD36, FABP3, FATP1 and FATP4) associated with decreased lipid oxidative pathway (citrate synthase and ß-HAD activities) and impaired lipogenesis (decreased triglyceride and free fatty acid content), indicating a role of mstn in muscle lipid metabolism. We further analyzed phospholipid classes and fatty acid composition by chromatographic methods in muscle and mitochondrial membranes. Mstn KO mice showed increased levels of saturated and polyunsaturated fatty acids at the expense of monounsaturated fatty acids. We also demonstrated, in this phenotype, a reduction in cardiolipin proportion in mitochondrial membrane versus the proportion of others phospholipids, in relation with a decrease in the expression of phosphatidylglycerolphosphate synthase and cardiolipin synthase, enzymes involved in cardiolipin synthesis. These data illustrate the importance of lipids as a link by which MSTN deficiency can impact mitochondrial bioenergetics in skeletal muscle.


Assuntos
Ácidos Graxos/metabolismo , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Miostatina/deficiência , 3-Hidroxiacil-CoA Desidrogenases/genética , 3-Hidroxiacil-CoA Desidrogenases/metabolismo , Animais , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Citrato (si)-Sintase/genética , Citrato (si)-Sintase/metabolismo , Ácidos Graxos/genética , Masculino , Camundongos , Camundongos Knockout , Mitocôndrias Musculares/genética , Mitocôndrias Musculares/patologia , Músculo Esquelético/patologia , Oxirredução
7.
Am J Physiol Endocrinol Metab ; 307(11): E983-93, 2014 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-25315696

RESUMO

REDD1 (regulated in development and DNA damage response 1) has been proposed to inhibit the mechanistic target of rapamycin complex 1 (mTORC1) during in vitro hypoxia. REDD1 expression is low under basal conditions but is highly increased in response to several catabolic stresses, like hypoxia and glucocorticoids. However, REDD1 function seems to be tissue and stress dependent, and its role in skeletal muscle in vivo has been poorly characterized. Here, we investigated the effect of REDD1 deletion on skeletal muscle mass, protein synthesis, proteolysis, and mTORC1 signaling pathway under basal conditions and after glucocorticoid administration. Whereas skeletal muscle mass and typology were unchanged between wild-type (WT) and REDD1-null mice, oral gavage with dexamethasone (DEX) for 7 days reduced tibialis anterior and gastrocnemius muscle weights as well as tibialis anterior fiber size only in WT. Similarly, REDD1 deletion prevented the inhibition of protein synthesis and mTORC1 activity (assessed by S6, 4E-BP1, and ULK1 phosphorylation) observed in gastrocnemius muscle of WT mice following single DEX administration for 5 h. However, our results suggest that REDD1-mediated inhibition of mTORC1 in skeletal muscle is not related to the modulation of the binding between TSC2 and 14-3-3. In contrast, our data highlight a new mechanism involved in mTORC1 inhibition linking REDD1, Akt, and PRAS40. Altogether, these results demonstrated in vivo that REDD1 is required for glucocorticoid-induced inhibition of protein synthesis via mTORC1 downregulation. Inhibition of REDD1 may thus be a strategy to limit muscle loss in glucocorticoid-mediated atrophy.


Assuntos
Dexametasona , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/genética , Fatores de Transcrição/genética , Fatores de Transcrição/fisiologia , Animais , Corticosterona/metabolismo , Fezes/química , Feminino , Camundongos , Contração Muscular/fisiologia , Músculo Esquelético/patologia , Atrofia Muscular/patologia , Proteólise , RNA Mensageiro/biossíntese , RNA Mensageiro/genética
8.
J Cell Sci ; 125(Pt 24): 6147-56, 2012 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-23132926

RESUMO

Protection of satellite cells from cytotoxic damages is crucial to ensure efficient adult skeletal muscle regeneration and to improve therapeutic efficacy of cell transplantation in degenerative skeletal muscle diseases. It is therefore important to identify and characterize molecules and their target genes that control the viability of muscle stem cells. Recently, we demonstrated that high aldehyde dehydrogenase activity is associated with increased viability of human myoblasts. In addition to its detoxifying activity, aldehyde dehydrogenase can also catalyze the irreversible oxidation of vitamin A to retinoic acid; therefore, we examined whether retinoic acid is important for myoblast viability. We showed that when exposed to oxidative stress induced by hydrogen peroxide, adherent human myoblasts entered apoptosis and lost their capacity for adhesion. Pre-treatment with retinoic acid reduced the cytotoxic damage ex vivo and enhanced myoblast survival in transplantation assays. The effects of retinoic acid were maintained in dystrophic myoblasts derived from facioscapulohumeral patients. RT-qPCR analysis of antioxidant gene expression revealed glutathione peroxidase 3 (Gpx3), a gene encoding an antioxidant enzyme, as a potential retinoic acid target gene in human myoblasts. Knockdown of Gpx3 using short interfering RNA induced elevation in reactive oxygen species and cell death. The anti-cytotoxic effects of retinoic acid were impaired in GPx3-inactivated myoblasts, which indicates that GPx3 regulates the antioxidative effects of retinoic acid. Therefore, retinoid status and GPx3 levels may have important implications for the viability of human muscle stem cells.


Assuntos
Glutationa Peroxidase/genética , Mioblastos/citologia , Mioblastos/enzimologia , Adulto , Animais , Antioxidantes/farmacologia , Apoptose , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Células Cultivadas , Técnicas de Silenciamento de Genes , Glutationa Peroxidase/deficiência , Glutationa Peroxidase/metabolismo , Humanos , Camundongos , Camundongos SCID , Mioblastos/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Tretinoína/farmacologia
9.
Cell Physiol Biochem ; 34(4): 1241-59, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25277978

RESUMO

BACKGROUND/AIMS: Overexpression of Gasp-1, an inhibitor of myostatin, leads to a hypermuscular phenotype due to hypertrophy rather than hyperplasia in mice. However to date, the cellular and molecular mechanisms underlying this phenotype are not investigated. METHODS: Skeletal muscles of overexpressing Gasp-1 mice, called Tg(Gasp-1) mice, were analyzed by histological methods. Satellite cell-derived myoblasts from these mice were used to investigate the molecular mechanisms. RESULTS: We demonstrated that hypertrophy in Tg(Gasp-1) mice was related to a myonuclear accretion during the first 3 postnatal weeks and an activation of the pro-hypertrophic Akt/mTORC/p70S6K signaling. In accordance with these results, we showed that overexpressing Gasp-1 primary myoblasts proliferated faster and myonuclei average per myotube was increased during differentiation. Molecular analysis revealed that Gasp-1 overexpression resulted in increased myostatin expression related to its auto-regulation. Despite its inhibition, myostatin led to Pax7 deregulation through its non-canonical Erk1/2 signaling pathway. Consistent with this, inhibition of Erk1/2 signaling pathway as well as neutralization of secreted myostatin rescue the Pax7 expression in overexpressing Gasp-1 myoblasts. CONCLUSION: Our study shows that myostatin is able to act independently of its canonical pathway to regulate the Pax7 expression. Altogether, our results indicate that myostatin could regulate muscle development despite its protein inhibition.


Assuntos
Proteínas de Transporte/genética , Hiperplasia/genética , Miostatina/genética , Regulação para Cima/genética , Animais , Diferenciação Celular/genética , Hiperplasia/embriologia , Hipertrofia/genética , Hipertrofia/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , Mioblastos/metabolismo , Fator de Transcrição PAX7/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/genética
10.
Am J Physiol Endocrinol Metab ; 302(8): E1000-8, 2012 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-22318951

RESUMO

Loss of myostatin (mstn) function leads to a decrease in mitochondrial content, a reduced expression of cytochrome c oxidase, and a lower citrate synthase activity in skeletal muscle. These data suggest functional or ultrastructural mitochondrial abnormalities that can impact on muscle endurance characteristics in such phenotype. To address this issue, we investigated subsarcolemmal and intermyofibrillar (IMF) mitochondrial activities, skeletal muscle redox homeostasis, and muscle fiber endurance quality in mstn-deficient mice [mstn knockout (KO)]. We report that lack of mstn induced a decrease in the coupling of IMF mitochondria respiration, with significantly higher basal oxygen consumption. No lysis of mitochondrial cristae or excessive swelling were observed in mstn KO mice compared with wild-type (WT) mice. Concerning redox status, mstn KO gastrocnemius exhibited a significant decrease in lipid peroxidation levels (-56%; P < 0.01 vs. WT) together with a significant upregulation of the antioxidant glutathione system. In contrast, superoxide dismutase and catalase activities were altered in mstn KO, gastrocnemius and soleus with a reduction of up to 80% compared with WT animals. The force production observed after contractile endurance test was significantly lower in extensor digitorum longus and soleus muscles of mstn KO mice compared with the controls (17 ± 3 and 36 ± 5% vs. 28 ± 4 and 56 ± 5%, respectively, P < 0.05). Together, these findings indicate that, besides an increased skeletal muscle mass, genetic mstn inhibition has differential effects on redox homeostasis and mitochondrial function that would have functional consequences on muscle response to endurance exercise.


Assuntos
Tolerância ao Exercício , Mitocôndrias Musculares/metabolismo , Contração Muscular , Miofibrilas/metabolismo , Miostatina/metabolismo , Estresse Oxidativo , Animais , Biomarcadores/metabolismo , Citrato (si)-Sintase/metabolismo , Técnicas In Vitro , Peroxidação de Lipídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Eletrônica de Transmissão , Mitocôndrias Musculares/ultraestrutura , Desenvolvimento Muscular , Músculo Esquelético/enzimologia , Músculo Esquelético/metabolismo , Músculo Esquelético/ultraestrutura , Miofibrilas/ultraestrutura , Miostatina/genética , Oxirredução , Fosforilação Oxidativa
11.
Clin Exp Pharmacol Physiol ; 39(4): 364-72, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22300302

RESUMO

Accumulating evidence suggests that the calpain/calpastatin system is involved in skeletal muscle remodelling induced by ß(2) -adrenoceptor agonist treatment. In addition to other pathways, the Akt/mammalian target of rapamycin (mTOR) pathway, controlling protein synthesis, and the calcium/calmodulin-dependent protein kinase 2 (CamK2) and AMP-activated protein kinase (AMPK) pathways, recently identified as calpain substrates, could be relevant in ß(2) -adrenoceptor agonist-induced skeletal muscle remodelling. In the present study we investigated muscle hypertrophy and phenotypic shifts, as well as the molecular response of components of the Akt/mTOR pathway (i.e. Akt, eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), ribosomal protein S6 (rpS6), CamK2 and AMPK), in response to calpastatin overexpression in the skeletal muscle of mice treated with 1 mg/kg per day clenbuterol for 21 days. Using gene electrotransfer of a calpastatin expression vector into the tibialis anterior of adult mice, we found that calpastatin overexpression attenuates muscle hypertrophy and phenotypic shifts induced by clenbuterol treatment. At the molecular level, calpastatin overexpression markedly decreased calpain activity, but was ineffective in altering the phosphorylation of Akt, 4E-BP1 and rpS6. In contrast, calpastatin overexpression increased the protein expression of both total AMPK and total CamK2. In conclusion, the results support the contention that the calpain/calpastatin system plays a crucial role in skeletal muscle hypertrophy and phenotypic shifts under chronic clenbuterol treatment, with AMPK and CamK2 probably playing a minor role. Moreover, the calpastatin-induced inhibition of hypertrophy under clenbuterol treatment was not related to a decreased mTOR-dependent initiation of protein translation.


Assuntos
Proteínas de Ligação ao Cálcio/biossíntese , Calpaína/antagonistas & inibidores , Clembuterol/toxicidade , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Fenótipo , Animais , Proteínas de Ligação ao Cálcio/genética , Calpaína/metabolismo , Bovinos , Clembuterol/antagonistas & inibidores , Regulação da Expressão Gênica , Hipertrofia/induzido quimicamente , Hipertrofia/metabolismo , Hipertrofia/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos CBA , Músculo Esquelético/efeitos dos fármacos
12.
J Cachexia Sarcopenia Muscle ; 13(3): 1686-1703, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35277933

RESUMO

BACKGROUND: Cancer patients at advanced stages experience a severe depletion of skeletal muscle compartment together with a decrease in muscle function, known as cancer cachexia. Cachexia contributes to reducing quality of life, treatment efficiency, and lifespan of cancer patients. However, the systemic nature of the syndrome is poorly documented. Here, we hypothesize that glucocorticoids would be important systemic mediators of cancer cachexia. METHODS: To explore the role of glucocorticoids during cancer cachexia, biomolecular analyses were performed on several tissues (adrenal glands, blood, hypothalamus, liver, and skeletal muscle) collected from ApcMin/+ male mice, a mouse model of intestine and colon cancer, aged of 13 and 23 weeks, and compared with wild type age-matched C57BL/6J littermates. RESULTS: Twenty-three-week-old Apc mice recapitulated important features of cancer cachexia including body weight loss (-16%, P < 0.0001), muscle atrophy (gastrocnemius muscle: -53%, P < 0.0001), and weakness (-50% in tibialis anterior muscle force, P < 0.0001), increased expression of atrogens (7-fold increase in MuRF1 transcript level, P < 0.0001) and down-regulation of Akt-mTOR pathway (3.3-fold increase in 4EBP1 protein content, P < 0.0001), together with a marked transcriptional rewiring of hepatic metabolism toward an increased expression of gluconeogenic genes (Pcx: +90%, Pck1: +85%), and decreased expression of glycolytic (Slc2a2: -40%, Gk: -30%, Pklr: -60%), ketogenic (Hmgcs2: -55%, Bdh1: -80%), lipolytic/fatty oxidation (Lipe: -50%, Mgll: -60%, Cpt2: -60%, Hadh: -30%), and lipogenic (Acly: -30%, Acacb: -70%, Fasn: -45%) genes. The hypothalamic pituitary-adrenal axis was activated, as evidenced by the increase in the transcript levels of genes encoding corticotropin-releasing hormone in the hypothalamus (2-fold increase, P < 0.01), adrenocorticotropic hormone receptor (3.4-fold increase, P < 0.001), and steroid biosynthesis enzymes (Cyp21a1, P < 0.0001, and Cyp11b1, P < 0.01) in the adrenal glands, as well as by the increase in corticosterone level in the serum (+73%, P < 0.05), skeletal muscle (+17%, P < 0.001), and liver (+24%, P < 0.05) of cachectic 23-week-old Apc mice. A comparative transcriptional analysis with dexamethasone-treated C57BL/6J mice indicated that the activation of the hypothalamic-pituitary-adrenal axis in 23-week-old ApcMin/+ mice was significantly associated with the transcription of glucocorticoid-responsive genes in skeletal muscle (P < 0.05) and liver (P < 0.001). The transcriptional regulation of glucocorticoid-responsive genes was also observed in the gastrocnemius muscle of Lewis lung carcinoma tumour-bearing mice and in KPC mice (tibialis anterior muscle and liver). CONCLUSIONS: These findings highlight the role of the hypothalamic-pituitary-adrenal-glucocorticoid pathway in the transcriptional regulation of skeletal muscle catabolism and hepatic metabolism during cancer cachexia. They also provide the paradigm for the design of new therapeutic strategies.


Assuntos
Carcinoma Pulmonar de Lewis , Sistema Hipófise-Suprarrenal , Idoso , Animais , Caquexia/genética , Caquexia/metabolismo , Carcinoma Pulmonar de Lewis/patologia , Expressão Gênica , Glucocorticoides , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/patologia , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/patologia , Sistema Hipófise-Suprarrenal/metabolismo , Sistema Hipófise-Suprarrenal/patologia , Qualidade de Vida
13.
Meat Sci ; 185: 108726, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34973590

RESUMO

Myostatin deficiency leads to extensive skeletal muscle hypertrophy, but its consequence on post-mortem muscle proteolysis is unknown. Here, we compared muscle myofibrillar protein degradation, and autophagy, ubiquitin-proteasome and Ca2+-dependent proteolysis relative to the energetic and redox status in wild-type (WT) and myostatin knock-out mice (KO) during early post-mortem storage. KO muscles showed higher degradation of myofibrillar proteins in the first 24 h after death, associated with preserved antioxidant status, compared with WT muscles. Analysis of key autophagy and ubiquitin-proteasome system markers indicated that these two pathways were not upregulated in post-mortem muscle (both genotypes), but basal autophagic flux and ATP content were lower in KO muscles. Proteasome and caspase activities were not different between WT and KO mice. Conversely, calpain activity was higher in KO muscles, concomitantly with higher troponin T and desmin degradation. Altogether, these results suggest that calpains but not the autophagy, proteasome and caspase systems, explain the difference in post-mortem muscle protein proteolysis between both genotypes.


Assuntos
Calpaína , Miostatina , Animais , Calpaína/genética , Calpaína/metabolismo , Inativação Gênica , Camundongos , Músculo Esquelético/metabolismo , Miostatina/genética , Proteólise
14.
Am J Physiol Cell Physiol ; 300(5): C1122-38, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21248078

RESUMO

Expression of Wnt proteins is known to be important for developmental processes such as embryonic pattern formation and determination of cell fate. Previous studies have shown that Wn4 was involved in the myogenic fate of somites, in the myogenic proliferation, and differentiation of skeletal muscle. However, the function of this factor in adult muscle homeostasis remains not well understood. Here, we focus on the roles of Wnt4 during C2C12 myoblasts and satellite cells differentiation. We analyzed its myogenic activity, its mechanism of action, and its interaction with the anti-myogenic factor myostatin during differentiation. Established expression profiles indicate clearly that both types of cells express a few Wnts, and among these, only Wnt4 was not or barely detected during proliferation and was strongly induced during differentiation. As attested by myogenic factors expression pattern analysis and fusion index determination, overexpression of Wnt4 protein caused a strong increase in satellite cells and C2C12 myoblast differentiation leading to hypertrophic myotubes. By contrast, exposure of satellite and C2C12 cells to small interfering RNA against Wnt4 strongly diminished this process, confirming the myogenic activity of Wnt4. Moreover, we reported that Wnt4, which is usually described as a noncanonical Wnt, activates the canonical ß-catenin pathway during myogenic differentiation in both cell types and that this factor regulates negatively the expression of myostatin and the regulating pathways associated with myostatin. Interestingly, we found that recombinant myostatin was sufficient to antagonize the differentiation-promoting activities of Wnt4. Reciprocally, we also found that the genetic deletion of myostatin renders the satellite cells refractory to the hypertrophic effect of Wnt4. These results suggest that the Wnt4-induced decrease of myostatin plays a functional role during hypertrophy. We propose that Wnt4 protein may be a key factor that regulates the extent of differentiation in satellite and C2C12 cells.


Assuntos
Desenvolvimento Muscular/fisiologia , Miostatina/metabolismo , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Perfilação da Expressão Gênica , Masculino , Camundongos , Desenvolvimento Muscular/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , RNA Interferente Pequeno/farmacologia , Células Satélites de Músculo Esquelético/efeitos dos fármacos , Células Satélites de Músculo Esquelético/metabolismo , Proteína Wnt4
15.
J Cell Biochem ; 112(12): 3531-42, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21769921

RESUMO

Myostatin deficiency leads in skeletal muscle overgrowth but the precise molecular mechanisms underlying this hypertrophy are not well understood. In this study, to gain insight into the role of endogenous myostatin in the translational regulation, we used an in vitro model of cultured satellite cells derived from myostatin knock-out mice. Our results show that myostatin knock-out myotubes are larger than control myotubes and that this phenotype is associated with an increased activation of the Akt/mTOR signaling pathway, a known regulator of muscle hypertrophy. These results demonstrate that hypertrophy due to myostatin deficiency is preserved in vitro and suggest that myostatin deletion results in an increased protein synthesis. Accordingly, the rates of global RNA content, polysome formation and protein synthesis are all increased in myostatin-deficient myotubes while they are counteracted by the addition of recombinant myostatin. We furthermore demonstrated that genetic deletion of myostatin stimulates cap-dependent translation by positively regulating assembly of the translation preinitiation complex. Together the data indicate that myostatin controls muscle hypertrophy in part by regulating protein synthesis initiation rates, that is, translational efficiency.


Assuntos
Fibras Musculares Esqueléticas/metabolismo , Miostatina/antagonistas & inibidores , Biossíntese de Proteínas , Animais , Sequência de Bases , Western Blotting , Linhagem Celular , Primers do DNA , Imunofluorescência , Camundongos , Camundongos Knockout , Fibras Musculares Esqueléticas/enzimologia , Miostatina/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
16.
Can J Physiol Pharmacol ; 89(2): 117-25, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21326343

RESUMO

Calpains are Ca2+ cysteine proteases that have been proposed to be involved in the cytoskeletal remodeling and wasting of skeletal muscle. Cumulative evidence also suggests that ß2-agonists can lead to skeletal muscle hypertrophy through a mechanism probably related to calcium-dependent proteolytic enzyme. The aim of our study was to monitor calpain activity as a function of clenbuterol treatment in both slow and fast phenotype rat muscles. For this purpose, for 21 days we followed the time course of the calpain activity and of the ubiquitous calpain 1 and 2 autolysis, as well as muscle remodeling in the extensor digitorum longus (EDL) and soleus muscles of male Wistar rats treated daily with clenbuterol (4 mg·kg-1). A slow to fast fiber shift was observed in both the EDL and soleus muscles after 9 days of treatment, while hypertrophy was observed only in EDL after 9 days of treatment. Soleus muscle but not EDL muscle underwent an early apoptonecrosis phase characterized by hematoxylin and eosin staining. Total calpain activity was increased in both the EDL and soleus muscles of rats treated with clenbuterol. Moreover, calpain 1 autolysis increased significantly after 14 days in the EDL, but not in the soleus. Calpain 2 autolysis increased significantly in both muscles 6 hours after the first clenbuterol injection, indicating that clenbuterol-induced calpain 2 autolysis occurred earlier than calpain 1 autolysis. Together, these data suggest a preferential involvement of calpain 2 autolysis compared with calpain 1 autolysis in the mechanisms underlying the clenbuterol-induced skeletal muscle remodeling.


Assuntos
Calpaína/metabolismo , Clembuterol/farmacologia , Fibras Musculares de Contração Rápida/efeitos dos fármacos , Fibras Musculares de Contração Rápida/enzimologia , Fibras Musculares de Contração Lenta/efeitos dos fármacos , Fibras Musculares de Contração Lenta/enzimologia , Agonistas Adrenérgicos beta/farmacologia , Agonistas Adrenérgicos beta/toxicidade , Animais , Autólise/tratamento farmacológico , Autólise/enzimologia , Morte Celular/efeitos dos fármacos , Clembuterol/toxicidade , Hipertrofia/induzido quimicamente , Masculino , Células Musculares/metabolismo , Fibras Musculares de Contração Rápida/patologia , Fibras Musculares de Contração Lenta/patologia , Ratos , Ratos Wistar , Regeneração/efeitos dos fármacos
17.
Nutrients ; 13(11)2021 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-34836120

RESUMO

Gut microbiota, a major contributor to human health, is influenced by physical activity and diet, and displays a functional cross-talk with skeletal muscle. Conversely, few data are available on the impact of hypoactivity, although sedentary lifestyles are widespread and associated with negative health and socio-economic impacts. The study aim was to determine the effect of Dry Immersion (DI), a severe hypoactivity model, on the human gut microbiota composition. Stool samples were collected from 14 healthy men before and after 5 days of DI to determine the gut microbiota taxonomic profiles by 16S metagenomic sequencing in strictly controlled dietary conditions. The α and ß diversities indices were unchanged. However, the operational taxonomic units associated with the Clostridiales order and the Lachnospiraceae family, belonging to the Firmicutes phylum, were significantly increased after DI. Propionate, a short-chain fatty acid metabolized by skeletal muscle, was significantly reduced in post-DI stool samples. The finding that intestine bacteria are sensitive to hypoactivity raises questions about their impact and role in chronic sedentary lifestyles.


Assuntos
Microbioma Gastrointestinal/fisiologia , Descanso/fisiologia , Comportamento Sedentário , Adulto , Fezes/química , Fezes/microbiologia , Voluntários Saudáveis , Humanos , Imersão/fisiopatologia , Masculino , Propionatos/metabolismo , Simulação de Ausência de Peso
18.
J Int Soc Sports Nutr ; 17(1): 58, 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-33198764

RESUMO

BACKGROUND: Owing to its strength-building and adaptogenic properties, Rhaponticum carthamoides (Rha) has been commonly used by elite Soviet and Russian athletes. Rhodiola rosea (Rho) is known to reduce physical and mental fatigue and improve endurance performance. However, the association of these two nutritional supplements with resistance exercise performance has never been tested. Resistance exercise is still the best way to stimulate protein synthesis and induce chronic muscle adaptations. The aim of this study was to investigate the acute and chronic effects of resistance exercise coupled with Rha and Rho supplementation on protein synthesis, muscle phenotype, and physical performance. METHODS: For the acute study, fifty-six rats were assigned to either a trained control group or one of the groups treated with specific doses of Rha and/or Rho. Each rats performed a single bout of climbing resistance exercise. The supplements were administered immediately after exercise by oral gavage. Protein synthesis was measured via puromycin incorporation. For the chronic study, forty rats were assigned to either the control group or one of the groups treated with doses adjusted from the acute study results. The rats were trained five times per week for 4 weeks with the same bout of climbing resistance exercise with additionals loads. Rha + Rho supplement was administered immediately after each training by oral gavage. RESULTS: The findings of the acute study indicated that Rha and Rha + Rho supplementation after resistance exercise stimulated protein synthesis more than resistance exercise alone (p < 0.05). After 4 weeks of training, the mean power performance was increased in the Rha + Rho and Rha-alone groups (p < 0.05) without any significant supplementation effect on muscle weight or fiber cross-sectional area. A tendency towards an increase in type I/ type II fiber ratio was observed in Rha/Rho-treated groups compared to that in the trained control group. CONCLUSION: Rhodiola and Rhaponticum supplementation after resistance exercise could synergistically improve protein synthesis, muscle phenotype and physical performance.


Assuntos
Leuzea/química , Proteínas Musculares/biossíntese , Músculo Esquelético/efeitos dos fármacos , Extratos Vegetais/farmacologia , Treinamento Resistido , Rhodiola/química , Animais , Músculo Esquelético/anatomia & histologia , Músculo Esquelético/metabolismo , Tamanho do Órgão , Desempenho Físico Funcional , Puromicina/metabolismo , Ratos , Ratos Wistar
19.
Curr Genomics ; 8(7): 415-22, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19412331

RESUMO

Myostatin is an endogenous, negative regulator of muscle growth determining both muscle fiber number and size. The myostatin pathway is conserved across diverse species ranging from zebrafish to humans. Experimental models of muscle growth and regeneration have implicated myostatin as an important mediator of catabolic pathways in muscle cells. Inhibition of this pathway has emerged as a promising therapy for muscle wasting. Here we discuss the recent developments and the controversies in myostatin research, focusing on the molecular and cellular mechanisms underlying the actions of myostatin on skeletal muscle and the potential therapeutic role of myostatin on muscle-related disorders.

20.
Mini Rev Med Chem ; 6(7): 765-70, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16842126

RESUMO

Myostatin is a negative regulator of muscle mass. Important advances in our understanding of the complex biology of this factor have revealed the therapeutic potential of antagonizing the myostatin pathway. Here we present the rationale for evaluating anti-myostatin therapies in human muscle-wasting disorders.


Assuntos
Fator de Crescimento Transformador beta/metabolismo , Tecido Adiposo/metabolismo , Animais , Humanos , Músculos/metabolismo , Distrofias Musculares/metabolismo , Miostatina , Rabdomiossarcoma/metabolismo , Rabdomiossarcoma/patologia , Transdução de Sinais
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