α−Calcitonin gene-related peptide inhibits autophagy and calpain systems and maintains the stability of neuromuscular junction in denervated muscles
Objective: Although it is well established that a-calcitonin gene-related peptide (CGRP) stabilizes muscle-type cholinergic receptors nicotinic subunits (AChR), the underlying mechanism by which this neuropeptide regulates muscle protein metabolism and neuromuscular junction (NMJ) morphology is uncl...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-10-01
|
| Series: | Molecular Metabolism |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877819302546 |
| id |
doaj-72ee95033dec4423a1100805f479e865 |
|---|---|
| record_format |
Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Juliano Machado Wilian A. Silveira Dawit A. Gonçalves Aline Zanatta Schavinski Muzamil M. Khan Neusa M. Zanon Mauricio Berriel Diaz Rüdiger Rudolf Isis C. Kettelhut Luiz C. Navegantes |
| spellingShingle |
Juliano Machado Wilian A. Silveira Dawit A. Gonçalves Aline Zanatta Schavinski Muzamil M. Khan Neusa M. Zanon Mauricio Berriel Diaz Rüdiger Rudolf Isis C. Kettelhut Luiz C. Navegantes α−Calcitonin gene-related peptide inhibits autophagy and calpain systems and maintains the stability of neuromuscular junction in denervated muscles Molecular Metabolism |
| author_facet |
Juliano Machado Wilian A. Silveira Dawit A. Gonçalves Aline Zanatta Schavinski Muzamil M. Khan Neusa M. Zanon Mauricio Berriel Diaz Rüdiger Rudolf Isis C. Kettelhut Luiz C. Navegantes |
| author_sort |
Juliano Machado |
| title |
α−Calcitonin gene-related peptide inhibits autophagy and calpain systems and maintains the stability of neuromuscular junction in denervated muscles |
| title_short |
α−Calcitonin gene-related peptide inhibits autophagy and calpain systems and maintains the stability of neuromuscular junction in denervated muscles |
| title_full |
α−Calcitonin gene-related peptide inhibits autophagy and calpain systems and maintains the stability of neuromuscular junction in denervated muscles |
| title_fullStr |
α−Calcitonin gene-related peptide inhibits autophagy and calpain systems and maintains the stability of neuromuscular junction in denervated muscles |
| title_full_unstemmed |
α−Calcitonin gene-related peptide inhibits autophagy and calpain systems and maintains the stability of neuromuscular junction in denervated muscles |
| title_sort |
α−calcitonin gene-related peptide inhibits autophagy and calpain systems and maintains the stability of neuromuscular junction in denervated muscles |
| publisher |
Elsevier |
| series |
Molecular Metabolism |
| issn |
2212-8778 |
| publishDate |
2019-10-01 |
| description |
Objective: Although it is well established that a-calcitonin gene-related peptide (CGRP) stabilizes muscle-type cholinergic receptors nicotinic subunits (AChR), the underlying mechanism by which this neuropeptide regulates muscle protein metabolism and neuromuscular junction (NMJ) morphology is unclear. Methods: To elucidate the mechanisms how CGRP controls NMJ stability in denervated mice skeletal muscles, we carried out physiological, pharmacological, and molecular analyses of atrophic muscles induced by sciatic nerve transection. Results: Here, we report that CGRP treatment in vivo abrogated the deleterious effects on NMJ upon denervation (DEN), an effect that was associated with suppression of skeletal muscle proteolysis, but not stimulation of protein synthesis. CGRP also blocked the DEN-induced increase in endocytic AChR vesicles and the elevation of autophagosomes per NMJ area. The treatment of denervated animals with rapamycin blocked the stimulatory effects of CGRP on mTORC1 and its inhibitory actions on autophagic flux and NMJ degeneration. Furthermore, CGRP inhibited the DEN-induced hyperactivation of Ca2+-dependent proteolysis, a degradative system that has been shown to destabilize NMJ. Consistently, calpain was found to be activated by cholinergic stimulation in myotubes leading to the dispersal of AChR clusters, an effect that was abolished by CGRP. Conclusion: Taken together, these data suggest that the inhibitory effect of CGRP on autophagy and calpain may represent an important mechanism for the preservation of synapse morphology when degradative machinery is exacerbated upon denervation conditions. Keyswords: Autophagy, CGRP, Calpain, Neuromuscular junction, Skeletal muscle |
| url |
http://www.sciencedirect.com/science/article/pii/S2212877819302546 |
| work_keys_str_mv |
AT julianomachado acalcitoningenerelatedpeptideinhibitsautophagyandcalpainsystemsandmaintainsthestabilityofneuromuscularjunctionindenervatedmuscles AT wilianasilveira acalcitoningenerelatedpeptideinhibitsautophagyandcalpainsystemsandmaintainsthestabilityofneuromuscularjunctionindenervatedmuscles AT dawitagoncalves acalcitoningenerelatedpeptideinhibitsautophagyandcalpainsystemsandmaintainsthestabilityofneuromuscularjunctionindenervatedmuscles AT alinezanattaschavinski acalcitoningenerelatedpeptideinhibitsautophagyandcalpainsystemsandmaintainsthestabilityofneuromuscularjunctionindenervatedmuscles AT muzamilmkhan acalcitoningenerelatedpeptideinhibitsautophagyandcalpainsystemsandmaintainsthestabilityofneuromuscularjunctionindenervatedmuscles AT neusamzanon acalcitoningenerelatedpeptideinhibitsautophagyandcalpainsystemsandmaintainsthestabilityofneuromuscularjunctionindenervatedmuscles AT mauricioberrieldiaz acalcitoningenerelatedpeptideinhibitsautophagyandcalpainsystemsandmaintainsthestabilityofneuromuscularjunctionindenervatedmuscles AT rudigerrudolf acalcitoningenerelatedpeptideinhibitsautophagyandcalpainsystemsandmaintainsthestabilityofneuromuscularjunctionindenervatedmuscles AT isisckettelhut acalcitoningenerelatedpeptideinhibitsautophagyandcalpainsystemsandmaintainsthestabilityofneuromuscularjunctionindenervatedmuscles AT luizcnavegantes acalcitoningenerelatedpeptideinhibitsautophagyandcalpainsystemsandmaintainsthestabilityofneuromuscularjunctionindenervatedmuscles |
| _version_ |
1725988301670711296 |
| spelling |
doaj-72ee95033dec4423a1100805f479e8652020-11-24T21:24:26ZengElsevierMolecular Metabolism2212-87782019-10-012891106α−Calcitonin gene-related peptide inhibits autophagy and calpain systems and maintains the stability of neuromuscular junction in denervated musclesJuliano Machado0Wilian A. Silveira1Dawit A. Gonçalves2Aline Zanatta Schavinski3Muzamil M. Khan4Neusa M. Zanon5Mauricio Berriel Diaz6Rüdiger Rudolf7Isis C. Kettelhut8Luiz C. Navegantes9Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil; Department of Biochemistry/Immunology, Ribeirão Preto Medical School/University of São Paulo, Ribeirão Preto, São Paulo, Brazil; Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, 85764, Neuherberg, Germany; Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, 69120, Heidelberg, GermanyDepartment of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, BrazilDepartment of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil; Department of Biochemistry/Immunology, Ribeirão Preto Medical School/University of São Paulo, Ribeirão Preto, São Paulo, BrazilDepartment of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, BrazilInstitute of Molecular and Cell Biology, University of Applied Sciences Mannheim, Mannheim, Germany; Institute of Medical Technology, University of Heidelberg and University of Applied Sciences Mannheim, Mannheim, GermanyDepartment of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, BrazilInstitute for Diabetes and Cancer (IDC), Helmholtz Center Munich, 85764, Neuherberg, Germany; Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, 69120, Heidelberg, GermanyInstitute of Molecular and Cell Biology, University of Applied Sciences Mannheim, Mannheim, Germany; Institute of Medical Technology, University of Heidelberg and University of Applied Sciences Mannheim, Mannheim, GermanyDepartment of Biochemistry/Immunology, Ribeirão Preto Medical School/University of São Paulo, Ribeirão Preto, São Paulo, BrazilDepartment of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil; Corresponding author. Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, 14049-900, Brazil.Objective: Although it is well established that a-calcitonin gene-related peptide (CGRP) stabilizes muscle-type cholinergic receptors nicotinic subunits (AChR), the underlying mechanism by which this neuropeptide regulates muscle protein metabolism and neuromuscular junction (NMJ) morphology is unclear. Methods: To elucidate the mechanisms how CGRP controls NMJ stability in denervated mice skeletal muscles, we carried out physiological, pharmacological, and molecular analyses of atrophic muscles induced by sciatic nerve transection. Results: Here, we report that CGRP treatment in vivo abrogated the deleterious effects on NMJ upon denervation (DEN), an effect that was associated with suppression of skeletal muscle proteolysis, but not stimulation of protein synthesis. CGRP also blocked the DEN-induced increase in endocytic AChR vesicles and the elevation of autophagosomes per NMJ area. The treatment of denervated animals with rapamycin blocked the stimulatory effects of CGRP on mTORC1 and its inhibitory actions on autophagic flux and NMJ degeneration. Furthermore, CGRP inhibited the DEN-induced hyperactivation of Ca2+-dependent proteolysis, a degradative system that has been shown to destabilize NMJ. Consistently, calpain was found to be activated by cholinergic stimulation in myotubes leading to the dispersal of AChR clusters, an effect that was abolished by CGRP. Conclusion: Taken together, these data suggest that the inhibitory effect of CGRP on autophagy and calpain may represent an important mechanism for the preservation of synapse morphology when degradative machinery is exacerbated upon denervation conditions. Keyswords: Autophagy, CGRP, Calpain, Neuromuscular junction, Skeletal musclehttp://www.sciencedirect.com/science/article/pii/S2212877819302546 |