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1.
J Physiol ; 598(23): 5351-5377, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32844438

RESUMO

KEY POINTS: Muscle-specific genetic ablation of p21-activated kinase (PAK)2, but not whole-body PAK1 knockout, impairs glucose tolerance in mice. Insulin-stimulated glucose uptake partly relies on PAK2 in glycolytic extensor digitorum longus muscle By contrast to previous reports, PAK1 is dispensable for insulin-stimulated glucose uptake in mouse muscle. ABSTRACT: The group I p21-activated kinase (PAK) isoforms PAK1 and PAK2 are activated in response to insulin in skeletal muscle and PAK1/2 signalling is impaired in insulin-resistant mouse and human skeletal muscle. Interestingly, PAK1 has been suggested to be required for insulin-stimulated glucose transporter 4 translocation in mouse skeletal muscle. Therefore, the present study aimed to examine the role of PAK1 in insulin-stimulated muscle glucose uptake. The pharmacological inhibitor of group I PAKs, IPA-3 partially reduced (-20%) insulin-stimulated glucose uptake in isolated mouse soleus muscle (P < 0.001). However, because there was no phenotype with genetic ablation of PAK1 alone, consequently, the relative requirement for PAK1 and PAK2 in whole-body glucose homeostasis and insulin-stimulated muscle glucose uptake was investigated. Whole-body respiratory exchange ratio was largely unaffected in whole-body PAK1 knockout (KO), muscle-specific PAK2 KO and in mice with combined whole-body PAK1 KO and muscle-specific PAK2 KO. By contrast, glucose tolerance was mildly impaired in mice lacking PAK2 specifically in muscle, but not PAK1 KO mice. Moreover, while PAK1 KO muscles displayed normal insulin-stimulated glucose uptake in vivo and in isolated muscle, insulin-stimulated glucose uptake was slightly reduced in isolated glycolytic extensor digitorum longus muscle lacking PAK2 alone (-18%) or in combination with PAK1 KO (-12%) (P < 0.05). In conclusion, glucose tolerance and insulin-stimulated glucose uptake partly rely on PAK2 in glycolytic mouse muscle, whereas PAK1 is dispensable for whole-body glucose homeostasis and insulin-stimulated muscle glucose uptake.


Assuntos
Insulina , Quinases Ativadas por p21 , Animais , Transporte Biológico , Glucose/metabolismo , Insulina/metabolismo , Camundongos , Músculo Esquelético/metabolismo , Quinases Ativadas por p21/metabolismo
2.
Mol Cell Biol ; 39(19)2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31308131

RESUMO

There is a lack of pharmacological interventions available for sarcopenia, a progressive age-associated loss of muscle mass, leading to a decline in mobility and quality of life. We found mTORC1 (mammalian target of rapamycin complex 1), a well-established positive modulator of muscle mass, to be surprisingly hyperactivated in sarcopenic muscle. Furthermore, partial inhibition of the mTORC1 pathway counteracted sarcopenia, as determined by observing an increase in muscle mass and fiber type cross-sectional area in select muscle groups, again surprising because mTORC1 signaling has been shown to be required for skeletal muscle mass gains in some models of hypertrophy. Additionally, several genes related to senescence were downregulated and gene expression indicators of neuromuscular junction denervation were diminished using a low dose of a "rapalog" (a pharmacological agent related to rapamycin). Therefore, partial mTORC1 inhibition may delay the progression of sarcopenia by directly and indirectly modulating multiple age-associated pathways, implicating mTORC1 as a therapeutic target to treat sarcopenia.


Assuntos
Everolimo/administração & dosagem , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Sarcopenia/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Regulação para Baixo , Everolimo/farmacologia , Redes Reguladoras de Genes/efeitos dos fármacos , Masculino , Músculo Esquelético/citologia , Músculo Esquelético/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Sarcopenia/metabolismo
3.
Skelet Muscle ; 9(1): 5, 2019 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-30791960

RESUMO

BACKGROUND: Group I Paks are serine/threonine kinases that function as major effectors of the small GTPases Rac1 and Cdc42, and they regulate cytoskeletal dynamics, cell polarity, and transcription. We previously demonstrated that Pak1 and Pak2 function redundantly to promote skeletal myoblast differentiation during postnatal development and regeneration in mice. However, the roles of Pak1 and Pak2 in adult muscle homeostasis are unknown. Choline kinase ß (Chk ß) is important for adult muscle homeostasis, as autosomal recessive mutations in CHKß are associated with two human muscle diseases, megaconial congenital muscular dystrophy and proximal myopathy with focal depletion of mitochondria. METHODS: We analyzed mice conditionally lacking Pak1 and Pak2 in the skeletal muscle lineage (double knockout (dKO) mice) over 1 year of age. Muscle integrity in dKO mice was assessed with histological stains, immunofluorescence, electron microscopy, and western blotting. Assays for mitochondrial respiratory complex function were performed, as was mass spectrometric quantification of products of choline kinase. Mice and cultured myoblasts deficient for choline kinase ß (Chk ß) were analyzed for Pak1/2 phosphorylation. RESULTS: dKO mice developed an age-related myopathy. By 10 months of age, dKO mouse muscles displayed centrally-nucleated myofibers, fibrosis, and signs of degeneration. Disease severity occurred in a rostrocaudal gradient, hindlimbs more strongly affected than forelimbs. A distinctive feature of this myopathy was elongated and branched intermyofibrillar (megaconial) mitochondria, accompanied by focal mitochondrial depletion in the central region of the fiber. dKO muscles showed reduced mitochondrial respiratory complex I and II activity. These phenotypes resemble those of rmd mice, which lack Chkß and are a model for human diseases associated with CHKß deficiency. Pak1/2 and Chkß activities were not interdependent in mouse skeletal muscle, suggesting a more complex relationship in regulation of mitochondria and muscle homeostasis. CONCLUSIONS: Conditional loss of Pak1 and Pak2 in mice resulted in an age-dependent myopathy with similarity to mice and humans with CHKß deficiency. Protein kinases are major regulators of most biological processes but few have been implicated in muscle maintenance or disease. Pak1/Pak2 dKO mice offer new insights into these processes.


Assuntos
Miopatias Mitocondriais/metabolismo , Músculo Esquelético/metabolismo , Quinases Ativadas por p21/metabolismo , Animais , Colina Quinase/metabolismo , Feminino , Masculino , Camundongos Knockout , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Miopatias Mitocondriais/genética , Miopatias Mitocondriais/patologia , Proteínas Mitocondriais/metabolismo , Músculo Esquelético/ultraestrutura , Quinases Ativadas por p21/genética
4.
Artigo em Inglês | MEDLINE | ID: mdl-28062562

RESUMO

Development of skeletal muscle is a multistage process that includes lineage commitment of multipotent progenitor cells, differentiation and fusion of myoblasts into multinucleated myofibers, and maturation of myofibers into distinct types. Lineage-specific transcriptional regulation lies at the core of this process, but myogenesis is also regulated by extracellular cues. Some of these cues are initiated by direct cell-cell contact between muscle precursor cells themselves or between muscle precursors and cells of other lineages. Examples of the latter include interaction of migrating neural crest cells with multipotent muscle progenitor cells, muscle interstitial cells with myoblasts, and neurons with myofibers. Among the signaling factors involved are Notch ligands and receptors, cadherins, Ig superfamily members, and Ephrins and Eph receptors. In this article we describe recent progress in this area and highlight open questions raised by the findings.


Assuntos
Músculo Esquelético/citologia , Animais , Diferenciação Celular , Fusão Celular , Linhagem da Célula , Humanos , Desenvolvimento Muscular/fisiologia
5.
Mol Cell Biol ; 37(4)2017 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-27920252

RESUMO

Skeletal myogenesis is regulated by signal transduction, but the factors and mechanisms involved are not well understood. The group I Paks Pak1 and Pak2 are related protein kinases and direct effectors of Cdc42 and Rac1. Group I Paks are ubiquitously expressed and specifically required for myoblast fusion in Drosophila We report that both Pak1 and Pak2 are activated during mammalian myoblast differentiation. One pathway of activation is initiated by N-cadherin ligation and involves the cadherin coreceptor Cdo with its downstream effector, Cdc42. Individual genetic deletion of Pak1 and Pak2 in mice has no overt effect on skeletal muscle development or regeneration. However, combined muscle-specific deletion of Pak1 and Pak2 results in reduced muscle mass and a higher proportion of myofibers with a smaller cross-sectional area. This phenotype is exacerbated after repair to acute injury. Furthermore, primary myoblasts lacking Pak1 and Pak2 display delayed expression of myogenic differentiation markers and myotube formation. These results identify Pak1 and Pak2 as redundant regulators of myoblast differentiation in vitro and in vivo and as components of the promyogenic Ncad/Cdo/Cdc42 signaling pathway.


Assuntos
Diferenciação Celular , Mioblastos Esqueléticos/citologia , Mioblastos Esqueléticos/enzimologia , Quinases Ativadas por p21/metabolismo , Animais , Caderinas/metabolismo , Moléculas de Adesão Celular/metabolismo , Linhagem Celular , Ativação Enzimática , Camundongos , Camundongos Knockout , Modelos Biológicos , Desenvolvimento Muscular , Células NIH 3T3 , Junção Neuromuscular/metabolismo , Tamanho do Órgão , Proteínas Proto-Oncogênicas c-akt/metabolismo , Regeneração , Transdução de Sinais , Sinapses/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
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