Calpain 3 deficiency affects SERCA expression and function in the skeletal muscle

Limb-girdle muscular dystrophy type 2A (LGMD2A) is a form of muscular dystrophy caused by mutations in calpain 3 (CAPN3). Several studies have implicated Ca2+ dysregulation as an underlying event in several muscular dystrophies, including LGMD2A. In this study we used mouse and human myotube culture...

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Main Authors:	Toral-Ojeda, Ivan, Aldanondo, Garazi, Lasa-Elgarresta, Jaione, Lasa-Fernández, Haizpea, Fernández-Torrón, Roberto, López de Munain, Adolfo, Vallejo-Illarramendi, Ainara
Format:	Online
Language:	English
Published:	Cambridge University Press 2016
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4836212/

id	pubmed-4836212
recordtype	oai_dc
spelling	pubmed-48362122016-05-09 Calpain 3 deficiency affects SERCA expression and function in the skeletal muscle Toral-Ojeda, Ivan Aldanondo, Garazi Lasa-Elgarresta, Jaione Lasa-Fernández, Haizpea Fernández-Torrón, Roberto López de Munain, Adolfo Vallejo-Illarramendi, Ainara Discovery Limb-girdle muscular dystrophy type 2A (LGMD2A) is a form of muscular dystrophy caused by mutations in calpain 3 (CAPN3). Several studies have implicated Ca2+ dysregulation as an underlying event in several muscular dystrophies, including LGMD2A. In this study we used mouse and human myotube cultures, and muscle biopsies in order to determine whether dysfunction of sarco/endoplasmatic Ca2+-ATPase (SERCA) is involved in the pathology of this disease. In CAPN3-deficient myotubes, we found decreased levels of SERCA 1 and 2 proteins, while mRNA levels remained comparable with control myotubes. Also, we found a significant reduction in SERCA function that resulted in impairment of Ca2+ homeostasis, and elevated basal intracellular [Ca2+] in human myotubes. Furthermore, small Ankyrin 1 (sAnk1), a SERCA1-binding protein that is involved in sarcoplasmic reticulum integrity, was also diminished in CAPN3-deficient fibres. Interestingly, SERCA2 protein was patently reduced in muscles from LGMD2A patients, while it was normally expressed in other forms of muscular dystrophy. Thus, analysis of SERCA2 expression may prove useful for diagnostic purposes as a potential indicator of CAPN3 deficiency in muscle biopsies. Altogether, our results indicate that CAPN3 deficiency leads to degradation of SERCA proteins and Ca2+ dysregulation in the skeletal muscle. While further studies are needed in order to elucidate the specific contribution of SERCA towards muscle degeneration in LGMD2A, this study constitutes a reasonable foundation for the development of therapeutic approaches targeting SERCA1, SERCA2 or sAnk1. Cambridge University Press 2016-04-08 /pmc/articles/PMC4836212/ /pubmed/27055500 http://dx.doi.org/10.1017/erm.2016.9 Text en © Cambridge University Press 2016 http://creativecommons.org/licenses/by/4.0/ This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Toral-Ojeda, Ivan Aldanondo, Garazi Lasa-Elgarresta, Jaione Lasa-Fernández, Haizpea Fernández-Torrón, Roberto López de Munain, Adolfo Vallejo-Illarramendi, Ainara
spellingShingle	Toral-Ojeda, Ivan Aldanondo, Garazi Lasa-Elgarresta, Jaione Lasa-Fernández, Haizpea Fernández-Torrón, Roberto López de Munain, Adolfo Vallejo-Illarramendi, Ainara Calpain 3 deficiency affects SERCA expression and function in the skeletal muscle
author_facet	Toral-Ojeda, Ivan Aldanondo, Garazi Lasa-Elgarresta, Jaione Lasa-Fernández, Haizpea Fernández-Torrón, Roberto López de Munain, Adolfo Vallejo-Illarramendi, Ainara
author_sort	Toral-Ojeda, Ivan
title	Calpain 3 deficiency affects SERCA expression and function in the skeletal muscle
title_short	Calpain 3 deficiency affects SERCA expression and function in the skeletal muscle
title_full	Calpain 3 deficiency affects SERCA expression and function in the skeletal muscle
title_fullStr	Calpain 3 deficiency affects SERCA expression and function in the skeletal muscle
title_full_unstemmed	Calpain 3 deficiency affects SERCA expression and function in the skeletal muscle
title_sort	calpain 3 deficiency affects serca expression and function in the skeletal muscle
description	Limb-girdle muscular dystrophy type 2A (LGMD2A) is a form of muscular dystrophy caused by mutations in calpain 3 (CAPN3). Several studies have implicated Ca2+ dysregulation as an underlying event in several muscular dystrophies, including LGMD2A. In this study we used mouse and human myotube cultures, and muscle biopsies in order to determine whether dysfunction of sarco/endoplasmatic Ca2+-ATPase (SERCA) is involved in the pathology of this disease. In CAPN3-deficient myotubes, we found decreased levels of SERCA 1 and 2 proteins, while mRNA levels remained comparable with control myotubes. Also, we found a significant reduction in SERCA function that resulted in impairment of Ca2+ homeostasis, and elevated basal intracellular [Ca2+] in human myotubes. Furthermore, small Ankyrin 1 (sAnk1), a SERCA1-binding protein that is involved in sarcoplasmic reticulum integrity, was also diminished in CAPN3-deficient fibres. Interestingly, SERCA2 protein was patently reduced in muscles from LGMD2A patients, while it was normally expressed in other forms of muscular dystrophy. Thus, analysis of SERCA2 expression may prove useful for diagnostic purposes as a potential indicator of CAPN3 deficiency in muscle biopsies. Altogether, our results indicate that CAPN3 deficiency leads to degradation of SERCA proteins and Ca2+ dysregulation in the skeletal muscle. While further studies are needed in order to elucidate the specific contribution of SERCA towards muscle degeneration in LGMD2A, this study constitutes a reasonable foundation for the development of therapeutic approaches targeting SERCA1, SERCA2 or sAnk1.
publisher	Cambridge University Press
publishDate	2016
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4836212/
_version_	1613567926697197568

Calpain 3 deficiency affects SERCA expression and function in the skeletal muscle

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