In vertebrates, the skeletal muscles of the body and their associated stem cells originate from muscle progenitor cells,during development. The specification of the muscles of the trunk, head and limbs, relies on the ...In vertebrates, the skeletal muscles of the body and their associated stem cells originate from muscle progenitor cells,during development. The specification of the muscles of the trunk, head and limbs, relies on the activity of distinctgenetic hierarchies. The major regulators of trunk and limb muscle specification are the paired-homeobox transcriptionfactors PAX3 and PAX7. Distinct gene regulatory networks drive the formation of the different muscles of thehead. Despite the redeployment of diverse upstream regulators of muscle progenitor differentiation, the commitmenttowards the myogenic fate requires the expression of the early myogenic regulatory factors MYF5, MRF4, MYOD andthe late differentiation marker MYOG. The expression of these genes is activated by muscle progenitors throughoutdevelopment, in several waves of myogenic differentiation, constituting the embryonic, fetal and postnatal phases ofmuscle growth. In order to achieve myogenic cell commitment while maintaining an undifferentiated pool of muscleprogenitors, several signaling pathways regulate the switch between proliferation and differentiation of myoblasts.The identification of the gene regulatory networks operating during myogenesis is crucial for the development ofin vitro protocols to differentiate pluripotent stem cells into myoblasts required for regenerative medicine.展开更多
The reduced diameter of skeletal myofibres is a hallmark of several congenital myopathies,yet the underlying cellular and molecular mechanisms remain elusive.In this study,we investigate the role of HACD1/PTPLA,which ...The reduced diameter of skeletal myofibres is a hallmark of several congenital myopathies,yet the underlying cellular and molecular mechanisms remain elusive.In this study,we investigate the role of HACD1/PTPLA,which is involved in the elongation of the very long chain fatty acids,in muscle fibre formation.In humans and dogs,HACD1 deficiency leads to a congenital myopathy with fibre size disproportion associated with a generalized muscleweakness.Throughanalysis of HACD1-deficient Labradors,Hacd1-knockout mice,and Hacd1-deficient myoblasts,we provide evidence that HACD1 promotes myoblast fusion during muscle development and regeneration.We further demonstrate that in normal differentiating myoblasts,expression of the catalytically active HACD1 isoform,which is encoded by a muscle-enriched splice variant,yields decreased lysophosphatidylcholine content,a potent inhibitor of myoblast fusion,and increased concentrations of≥C18 and monounsaturated fatty acids of phospholipids.These lipid modifications correlate with a reduction in plasma membrane rigidity.In conclusion,we propose that fusion impairment constitutes a novel,non-exclusive pathological mechanism operating in congenital myopathies and reveal that HACD1 is a key regulator of a lipid-dependent muscle fibre growth mechanism.展开更多
基金FR laboratory is supported by funding from Association Française contre les Myopathies(AFM)via TRANSLAMUSCLE(PROJECT 19507 and 22946)Agence Nationale pour la Recherche(ANR)grant Epimuscle(ANR 11 BSV201702)RHU CARMMA(ANR-15-RHUS-0003).
文摘In vertebrates, the skeletal muscles of the body and their associated stem cells originate from muscle progenitor cells,during development. The specification of the muscles of the trunk, head and limbs, relies on the activity of distinctgenetic hierarchies. The major regulators of trunk and limb muscle specification are the paired-homeobox transcriptionfactors PAX3 and PAX7. Distinct gene regulatory networks drive the formation of the different muscles of thehead. Despite the redeployment of diverse upstream regulators of muscle progenitor differentiation, the commitmenttowards the myogenic fate requires the expression of the early myogenic regulatory factors MYF5, MRF4, MYOD andthe late differentiation marker MYOG. The expression of these genes is activated by muscle progenitors throughoutdevelopment, in several waves of myogenic differentiation, constituting the embryonic, fetal and postnatal phases ofmuscle growth. In order to achieve myogenic cell commitment while maintaining an undifferentiated pool of muscleprogenitors, several signaling pathways regulate the switch between proliferation and differentiation of myoblasts.The identification of the gene regulatory networks operating during myogenesis is crucial for the development ofin vitro protocols to differentiate pluripotent stem cells into myoblasts required for regenerative medicine.
基金This work was supported by the Agence Nationale de la Recherche(ANR-12-JSV1-0005)the Association Franc¸aise contre les Myopathies(14577,15882,and 16143)+4 种基金the CNM Project(www.labradorcnm.com)the Alliance program(22866ZM)the Myotubular Trust and Grants-in-Aid for Scientific Research(B)to A.K.from Japan Society for the Promotion of Science(23370057)J.B.was supported by the French Ministry of Research and Technologies and the Universite´Paris 6(Paris)V.G.,A.P.,and A.R.were supported by the ANR,N.B-G.and I.B.were supported by the AFM,and G.W.was supported by the BBSRC CASE and the Myotubular Trust.
文摘The reduced diameter of skeletal myofibres is a hallmark of several congenital myopathies,yet the underlying cellular and molecular mechanisms remain elusive.In this study,we investigate the role of HACD1/PTPLA,which is involved in the elongation of the very long chain fatty acids,in muscle fibre formation.In humans and dogs,HACD1 deficiency leads to a congenital myopathy with fibre size disproportion associated with a generalized muscleweakness.Throughanalysis of HACD1-deficient Labradors,Hacd1-knockout mice,and Hacd1-deficient myoblasts,we provide evidence that HACD1 promotes myoblast fusion during muscle development and regeneration.We further demonstrate that in normal differentiating myoblasts,expression of the catalytically active HACD1 isoform,which is encoded by a muscle-enriched splice variant,yields decreased lysophosphatidylcholine content,a potent inhibitor of myoblast fusion,and increased concentrations of≥C18 and monounsaturated fatty acids of phospholipids.These lipid modifications correlate with a reduction in plasma membrane rigidity.In conclusion,we propose that fusion impairment constitutes a novel,non-exclusive pathological mechanism operating in congenital myopathies and reveal that HACD1 is a key regulator of a lipid-dependent muscle fibre growth mechanism.
