Dysregulated skeletal muscle myosin super-relaxation and energetics in male participants with type 2 diabetes mellitus.

Disrupted energy balance is critical for the onset and development of type 2 diabetes mellitus. Understanding of the exact underlying metabolic mechanisms remains incomplete, but skeletal muscle is thought to play an important pathogenic role. As the super-relaxed state of its most abundant protein,...

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Autores: Lewis, Christopher T A, Moreno-Justicia, Roger, Savoure, Lola, Calvo, Enrique, Bak, Agata, Laitila, Jenni, Seaborne, Robert A E, Larsen, Steen, Iwamoto, Hiroyuki, Cefis, Marina, Morais, Jose A, Gouspillou, Gilles, Alegre-Cebollada, Jorge, Hawke, Thomas J, Vazquez, Jesús, Adrover, Miquel, Marcangeli, Vincent, Hammad, Rami, Granet, Jordan, Gaudreau, Pierrette, Aubertin-Leheudre, Mylène, Bélanger, Marc, Robitaille, Richard, Deshmukh, Atul S, Ochala, Julien
Formato: artículo
Fecha de publicación:2025
País:España
Recursos:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/26846
Acesso em linha:https://hdl.handle.net/20.500.12105/26846
Access Level:acceso abierto
Palavra-chave:Diabetes
Metabolism
Myosin
Skeletal muscle
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spelling Dysregulated skeletal muscle myosin super-relaxation and energetics in male participants with type 2 diabetes mellitus.Lewis, Christopher T AMoreno-Justicia, RogerSavoure, LolaCalvo, EnriqueBak, AgataLaitila, JenniSeaborne, Robert A ELarsen, SteenIwamoto, HiroyukiCefis, MarinaMorais, Jose AGouspillou, GillesAlegre-Cebollada, JorgeHawke, Thomas JVazquez, JesúsAdrover, MiquelMarcangeli, VincentHammad, RamiGranet, JordanGaudreau, PierretteAubertin-Leheudre, MylèneBélanger, MarcRobitaille, RichardDeshmukh, Atul SOchala, JulienDiabetesMetabolismMyosinSkeletal muscleDisrupted energy balance is critical for the onset and development of type 2 diabetes mellitus. Understanding of the exact underlying metabolic mechanisms remains incomplete, but skeletal muscle is thought to play an important pathogenic role. As the super-relaxed state of its most abundant protein, myosin, regulates cellular energetics, we aimed to investigate whether it is altered in individuals with type 2 diabetes. We used vastus lateralis biopsy specimens (obtained from patients with type 2 diabetes and control participants with similar characteristics), and ran a combination of structural and functional assays consisting of loaded 2'- (or 3')-O-(N-methylanthraniloyl)-ATP (Mant-ATP) chase experiments, x-ray diffraction and LC-MS/MS proteomics in isolated muscle fibres. Our studies revealed a greater muscle myosin super-relaxation and decreased ATP demand in male participants with type 2 diabetes than in control participants. Subsequent proteomic analyses indicated that these (mal)adaptations probably originated from remodelled sarcomeric proteins and greater myosin glycation levels in patients than in control participants. Overall, our findings indicate a complex molecular dysregulation of myosin super-relaxed state and energy consumption in male participants with type 2 diabetes. Ultimately, pharmacological targeting of myosin could benefit skeletal muscle and whole-body metabolic health through enhancement of ATP consumption. The raw MS data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD053022.SpringerNovo Nordisk FoundationInstituto de Salud Carlos IIIMinisterio de Ciencia, Innovación y Universidades (España)Fundación ProCNICMinisterio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España)20252025-07-2320252025-08-0120252025-08-01research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/20.500.12105/26846reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)InglésengES MICIU AEI 501100011033ES CEX2020-001041 Not availableopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/268462026-06-12T12:43:37Z
dc.title.none.fl_str_mv Dysregulated skeletal muscle myosin super-relaxation and energetics in male participants with type 2 diabetes mellitus.
title Dysregulated skeletal muscle myosin super-relaxation and energetics in male participants with type 2 diabetes mellitus.
spellingShingle Dysregulated skeletal muscle myosin super-relaxation and energetics in male participants with type 2 diabetes mellitus.
Lewis, Christopher T A
Diabetes
Metabolism
Myosin
Skeletal muscle
title_short Dysregulated skeletal muscle myosin super-relaxation and energetics in male participants with type 2 diabetes mellitus.
title_full Dysregulated skeletal muscle myosin super-relaxation and energetics in male participants with type 2 diabetes mellitus.
title_fullStr Dysregulated skeletal muscle myosin super-relaxation and energetics in male participants with type 2 diabetes mellitus.
title_full_unstemmed Dysregulated skeletal muscle myosin super-relaxation and energetics in male participants with type 2 diabetes mellitus.
title_sort Dysregulated skeletal muscle myosin super-relaxation and energetics in male participants with type 2 diabetes mellitus.
dc.creator.none.fl_str_mv Lewis, Christopher T A
Moreno-Justicia, Roger
Savoure, Lola
Calvo, Enrique
Bak, Agata
Laitila, Jenni
Seaborne, Robert A E
Larsen, Steen
Iwamoto, Hiroyuki
Cefis, Marina
Morais, Jose A
Gouspillou, Gilles
Alegre-Cebollada, Jorge
Hawke, Thomas J
Vazquez, Jesús
Adrover, Miquel
Marcangeli, Vincent
Hammad, Rami
Granet, Jordan
Gaudreau, Pierrette
Aubertin-Leheudre, Mylène
Bélanger, Marc
Robitaille, Richard
Deshmukh, Atul S
Ochala, Julien
author Lewis, Christopher T A
author_facet Lewis, Christopher T A
Moreno-Justicia, Roger
Savoure, Lola
Calvo, Enrique
Bak, Agata
Laitila, Jenni
Seaborne, Robert A E
Larsen, Steen
Iwamoto, Hiroyuki
Cefis, Marina
Morais, Jose A
Gouspillou, Gilles
Alegre-Cebollada, Jorge
Hawke, Thomas J
Vazquez, Jesús
Adrover, Miquel
Marcangeli, Vincent
Hammad, Rami
Granet, Jordan
Gaudreau, Pierrette
Aubertin-Leheudre, Mylène
Bélanger, Marc
Robitaille, Richard
Deshmukh, Atul S
Ochala, Julien
author_role author
author2 Moreno-Justicia, Roger
Savoure, Lola
Calvo, Enrique
Bak, Agata
Laitila, Jenni
Seaborne, Robert A E
Larsen, Steen
Iwamoto, Hiroyuki
Cefis, Marina
Morais, Jose A
Gouspillou, Gilles
Alegre-Cebollada, Jorge
Hawke, Thomas J
Vazquez, Jesús
Adrover, Miquel
Marcangeli, Vincent
Hammad, Rami
Granet, Jordan
Gaudreau, Pierrette
Aubertin-Leheudre, Mylène
Bélanger, Marc
Robitaille, Richard
Deshmukh, Atul S
Ochala, Julien
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Novo Nordisk Foundation
Instituto de Salud Carlos III
Ministerio de Ciencia, Innovación y Universidades (España)
Fundación ProCNIC
Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España)
dc.subject.none.fl_str_mv Diabetes
Metabolism
Myosin
Skeletal muscle
topic Diabetes
Metabolism
Myosin
Skeletal muscle
description Disrupted energy balance is critical for the onset and development of type 2 diabetes mellitus. Understanding of the exact underlying metabolic mechanisms remains incomplete, but skeletal muscle is thought to play an important pathogenic role. As the super-relaxed state of its most abundant protein, myosin, regulates cellular energetics, we aimed to investigate whether it is altered in individuals with type 2 diabetes. We used vastus lateralis biopsy specimens (obtained from patients with type 2 diabetes and control participants with similar characteristics), and ran a combination of structural and functional assays consisting of loaded 2'- (or 3')-O-(N-methylanthraniloyl)-ATP (Mant-ATP) chase experiments, x-ray diffraction and LC-MS/MS proteomics in isolated muscle fibres. Our studies revealed a greater muscle myosin super-relaxation and decreased ATP demand in male participants with type 2 diabetes than in control participants. Subsequent proteomic analyses indicated that these (mal)adaptations probably originated from remodelled sarcomeric proteins and greater myosin glycation levels in patients than in control participants. Overall, our findings indicate a complex molecular dysregulation of myosin super-relaxed state and energy consumption in male participants with type 2 diabetes. Ultimately, pharmacological targeting of myosin could benefit skeletal muscle and whole-body metabolic health through enhancement of ATP consumption. The raw MS data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD053022.
publishDate 2025
dc.date.none.fl_str_mv 2025
2025-07-23
2025
2025-08-01
2025
2025-08-01
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/20.500.12105/26846
url https://hdl.handle.net/20.500.12105/26846
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv ES MICIU AEI 501100011033
ES CEX2020-001041 Not available
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Springer
publisher.none.fl_str_mv Springer
dc.source.none.fl_str_mv reponame:Repisalud
instname:Instituto de Salud Carlos III (ISCIII)
instname_str Instituto de Salud Carlos III (ISCIII)
reponame_str Repisalud
collection Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.812429

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