Loss of dysferlin or myoferlin results in differential defects in excitation–contraction coupling in mouse skeletal muscle

Abstract Muscular dystrophies are disorders characterized by progressive muscle loss and weakness that are both genotypically and phenotypically heterogenous. Progression of muscle disease arises from impaired regeneration, plasma membrane instability, defective membrane repair, and calcium mishandl...

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Autores principales:	David Y. Barefield, Jordan J. Sell, Ibrahim Tahtah, Samuel D. Kearns, Elizabeth M. McNally, Alexis R. Demonbreun
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/0ace02e8503f4803979e5eef97f341b7
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spelling	oai:doaj.org-article:0ace02e8503f4803979e5eef97f341b72021-12-02T16:36:36ZLoss of dysferlin or myoferlin results in differential defects in excitation–contraction coupling in mouse skeletal muscle10.1038/s41598-021-95378-92045-2322https://doaj.org/article/0ace02e8503f4803979e5eef97f341b72021-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-95378-9https://doaj.org/toc/2045-2322Abstract Muscular dystrophies are disorders characterized by progressive muscle loss and weakness that are both genotypically and phenotypically heterogenous. Progression of muscle disease arises from impaired regeneration, plasma membrane instability, defective membrane repair, and calcium mishandling. The ferlin protein family, including dysferlin and myoferlin, are calcium-binding, membrane-associated proteins that regulate membrane fusion, trafficking, and tubule formation. Mice lacking dysferlin (Dysf), myoferlin (Myof), and both dysferlin and myoferlin (Fer) on an isogenic inbred 129 background were previously demonstrated that loss of both dysferlin and myoferlin resulted in more severe muscle disease than loss of either gene alone. Furthermore, Fer mice had disordered triad organization with visibly malformed transverse tubules and sarcoplasmic reticulum, suggesting distinct roles of dysferlin and myoferlin. To assess the physiological role of disorganized triads, we now assessed excitation contraction (EC) coupling in these models. We identified differential abnormalities in EC coupling and ryanodine receptor disruption in flexor digitorum brevis myofibers isolated from ferlin mutant mice. We found that loss of dysferlin alone preserved sensitivity for EC coupling and was associated with larger ryanodine receptor clusters compared to wildtype myofibers. Loss of myoferlin alone or together with a loss of dysferlin reduced sensitivity for EC coupling, and produced disorganized and smaller ryanodine receptor cluster size compared to wildtype myofibers. These data reveal impaired EC coupling in Myof and Fer myofibers and slightly potentiated EC coupling in Dysf myofibers. Despite high homology, dysferlin and myoferlin have differential roles in regulating sarcotubular formation and maintenance resulting in unique impairments in calcium handling properties.David Y. BarefieldJordan J. SellIbrahim TahtahSamuel D. KearnsElizabeth M. McNallyAlexis R. DemonbreunNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q David Y. Barefield Jordan J. Sell Ibrahim Tahtah Samuel D. Kearns Elizabeth M. McNally Alexis R. Demonbreun Loss of dysferlin or myoferlin results in differential defects in excitation–contraction coupling in mouse skeletal muscle
description	Abstract Muscular dystrophies are disorders characterized by progressive muscle loss and weakness that are both genotypically and phenotypically heterogenous. Progression of muscle disease arises from impaired regeneration, plasma membrane instability, defective membrane repair, and calcium mishandling. The ferlin protein family, including dysferlin and myoferlin, are calcium-binding, membrane-associated proteins that regulate membrane fusion, trafficking, and tubule formation. Mice lacking dysferlin (Dysf), myoferlin (Myof), and both dysferlin and myoferlin (Fer) on an isogenic inbred 129 background were previously demonstrated that loss of both dysferlin and myoferlin resulted in more severe muscle disease than loss of either gene alone. Furthermore, Fer mice had disordered triad organization with visibly malformed transverse tubules and sarcoplasmic reticulum, suggesting distinct roles of dysferlin and myoferlin. To assess the physiological role of disorganized triads, we now assessed excitation contraction (EC) coupling in these models. We identified differential abnormalities in EC coupling and ryanodine receptor disruption in flexor digitorum brevis myofibers isolated from ferlin mutant mice. We found that loss of dysferlin alone preserved sensitivity for EC coupling and was associated with larger ryanodine receptor clusters compared to wildtype myofibers. Loss of myoferlin alone or together with a loss of dysferlin reduced sensitivity for EC coupling, and produced disorganized and smaller ryanodine receptor cluster size compared to wildtype myofibers. These data reveal impaired EC coupling in Myof and Fer myofibers and slightly potentiated EC coupling in Dysf myofibers. Despite high homology, dysferlin and myoferlin have differential roles in regulating sarcotubular formation and maintenance resulting in unique impairments in calcium handling properties.
format	article
author	David Y. Barefield Jordan J. Sell Ibrahim Tahtah Samuel D. Kearns Elizabeth M. McNally Alexis R. Demonbreun
author_facet	David Y. Barefield Jordan J. Sell Ibrahim Tahtah Samuel D. Kearns Elizabeth M. McNally Alexis R. Demonbreun
author_sort	David Y. Barefield
title	Loss of dysferlin or myoferlin results in differential defects in excitation–contraction coupling in mouse skeletal muscle
title_short	Loss of dysferlin or myoferlin results in differential defects in excitation–contraction coupling in mouse skeletal muscle
title_full	Loss of dysferlin or myoferlin results in differential defects in excitation–contraction coupling in mouse skeletal muscle
title_fullStr	Loss of dysferlin or myoferlin results in differential defects in excitation–contraction coupling in mouse skeletal muscle
title_full_unstemmed	Loss of dysferlin or myoferlin results in differential defects in excitation–contraction coupling in mouse skeletal muscle
title_sort	loss of dysferlin or myoferlin results in differential defects in excitation–contraction coupling in mouse skeletal muscle
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/0ace02e8503f4803979e5eef97f341b7
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Loss of dysferlin or myoferlin results in differential defects in excitation–contraction coupling in mouse skeletal muscle

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