Sarcolemmal targeting of nNOS mu improves contractile function of mdx muscle

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dc.contributor.authorRebolledo, Daniela L.
dc.contributor.authorKim, Min Jeong
dc.contributor.authorWhitehead, Nicholas P.
dc.contributor.authorAdams, Marvin E.
dc.contributor.authorFroehner, Stanley C.
dc.date.accessioned2024-01-10T12:42:17Z
dc.date.available2024-01-10T12:42:17Z
dc.date.issued2016
dc.description.abstractNitric oxide (NO) is a key regulator of skeletal muscle function and metabolism, including vasoregulation, mitochondrial function, glucose uptake, fatigue and excitation-contraction coupling. The main generator of NO in skeletal muscle is the muscle-specific form of neuronal nitric oxide synthase (nNOS mu) produced by the NOS1 gene. Skeletal muscle nNOS mu is predominantly localized at the sarcolemma by interaction with the dystrophin protein complex (DPC). In Duchenne muscular dystrophy (DMD), loss of dystrophin leads to the mislocalization of nNOS mu from the sarcolemma to the cytosol. This perturbation has been shown to impair contractile function and cause muscle fatigue in dystrophic (mdx) mice. Here, we investigated the effect of restoring sarcolemmal nNOS mu on muscle contractile function in mdx mice. To achieve this, we designed a modified form of nNOS mu (NOS-M) that is targeted to the sarcolemma by palmitoylation, even in the absence of the DPC. When expressed specifically in mdx skeletal muscle, NOS-M significantly attenuates force loss owing to damaging eccentric contractions and repetitive isometric contractions (fatigue), while also improving force recovery after fatigue. Expression of unmodified nNOS mu at similar levels does not lead to sarcolemmal association and fails to improve muscle function. Aside from the benefits of sarcolemmal-localized NO production, NOS-M also increased the surface membrane levels of utrophin and other DPC proteins, including beta-dystroglycan, alpha-syntrophin and alpha-dystrobrevin in mdx muscle. These results suggest that the expression of NOS-M in skeletal muscle may be therapeutically beneficial in DMD and other muscle diseases characterized by the loss of nNOS mu from the sarcolemma.
dc.description.funderCONICYT
dc.description.funderMECESUP
dc.description.funderCardiovascular Training grant from NHLBI
dc.description.funderRaymond and Beverly Sackler Foundation
dc.description.funderNational Institutes of Health
dc.description.funderNATIONAL HEART, LUNG, AND BLOOD INSTITUTE
dc.description.funderNATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
dc.fechaingreso.objetodigital2024-04-30
dc.format.extent9 páginas
dc.fuente.origenWOS
dc.identifier.doi10.1093/hmg/ddv466
dc.identifier.eissn1460-2083
dc.identifier.issn0964-6906
dc.identifier.pubmedidMEDLINE:26604149
dc.identifier.urihttps://doi.org/10.1093/hmg/ddv466
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/77499
dc.identifier.wosidWOS:000372147800013
dc.information.autorucCiencias Biológicas;Rebolledo D;S/I;142327
dc.issue.numero1
dc.language.isoen
dc.nota.accesocontenido parcial
dc.pagina.final166
dc.pagina.inicio158
dc.publisherOXFORD UNIV PRESS
dc.revistaHUMAN MOLECULAR GENETICS
dc.rightsacceso restringido
dc.subjectNITRIC-OXIDE-SYNTHASE
dc.subjectDUCHENNE MUSCULAR-DYSTROPHY
dc.subjectDEFICIENT SKELETAL-MUSCLE
dc.subjectNEURONAL NOS
dc.subjectS-NITROSYLATION
dc.subjectMEMBRANE DAMAGE
dc.subjectMICE
dc.subjectEXPRESSION
dc.subjectUTROPHIN
dc.subjectTRANSGENE
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleSarcolemmal targeting of nNOS mu improves contractile function of mdx muscle
dc.typeartículo
dc.volumen25
sipa.codpersvinculados142327
sipa.indexWOS
sipa.indexScopus
sipa.trazabilidadCarga SIPA;09-01-2024
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