Cargando…

Mitochondrial dysfunction and consequences in calpain-3-deficient muscle

BACKGROUND: Nonsense or loss-of-function mutations in the non-lysosomal cysteine protease calpain-3 result in limb-girdle muscular dystrophy type 2A (LGMD2A). While calpain-3 is implicated in muscle cell differentiation, sarcomere formation, and muscle cytoskeletal remodeling, the physiological basi...

Descripción completa

Detalles Bibliográficos
Autores principales: Jahnke, Vanessa E., Peterson, Jennifer M., Van Der Meulen, Jack H., Boehler, Jessica, Uaesoontrachoon, Kitipong, Johnston, Helen K., Defour, Aurelia, Phadke, Aditi, Yu, Qing, Jaiswal, Jyoti K., Nagaraju, Kanneboyina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730798/
https://www.ncbi.nlm.nih.gov/pubmed/33308300
http://dx.doi.org/10.1186/s13395-020-00254-1
_version_ 1783621766975848448
author Jahnke, Vanessa E.
Peterson, Jennifer M.
Van Der Meulen, Jack H.
Boehler, Jessica
Uaesoontrachoon, Kitipong
Johnston, Helen K.
Defour, Aurelia
Phadke, Aditi
Yu, Qing
Jaiswal, Jyoti K.
Nagaraju, Kanneboyina
author_facet Jahnke, Vanessa E.
Peterson, Jennifer M.
Van Der Meulen, Jack H.
Boehler, Jessica
Uaesoontrachoon, Kitipong
Johnston, Helen K.
Defour, Aurelia
Phadke, Aditi
Yu, Qing
Jaiswal, Jyoti K.
Nagaraju, Kanneboyina
author_sort Jahnke, Vanessa E.
collection PubMed
description BACKGROUND: Nonsense or loss-of-function mutations in the non-lysosomal cysteine protease calpain-3 result in limb-girdle muscular dystrophy type 2A (LGMD2A). While calpain-3 is implicated in muscle cell differentiation, sarcomere formation, and muscle cytoskeletal remodeling, the physiological basis for LGMD2A has remained elusive. METHODS: Cell growth, gene expression profiling, and mitochondrial content and function were analyzed using muscle and muscle cell cultures established from healthy and calpain-3-deficient mice. Calpain-3-deficient mice were also treated with PPAR-delta agonist (GW501516) to assess mitochondrial function and membrane repair. The unpaired t test was used to assess the significance of the differences observed between the two groups or treatments. ANOVAs were used to assess significance over time. RESULTS: We find that calpain-3 deficiency causes mitochondrial dysfunction in the muscles and myoblasts. Calpain-3-deficient myoblasts showed increased proliferation, and their gene expression profile showed aberrant mitochondrial biogenesis. Myotube gene expression analysis further revealed altered lipid metabolism in calpain-3-deficient muscle. Mitochondrial defects were validated in vitro and in vivo. We used GW501516 to improve mitochondrial biogenesis in vivo in 7-month-old calpain-3-deficient mice. This treatment improved satellite cell activity as indicated by increased MyoD and Pax7 mRNA expression. It also decreased muscle fatigability and reduced serum creatine kinase levels. The decreased mitochondrial function also impaired sarcolemmal repair in the calpain-3-deficient skeletal muscle. Improving mitochondrial activity by acute pyruvate treatment improved sarcolemmal repair. CONCLUSION: Our results provide evidence that calpain-3 deficiency in the skeletal muscle is associated with poor mitochondrial biogenesis and function resulting in poor sarcolemmal repair. Addressing this deficit by drugs that improve mitochondrial activity offers new therapeutic avenues for LGMD2A.
format Online
Article
Text
id pubmed-7730798
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-77307982020-12-11 Mitochondrial dysfunction and consequences in calpain-3-deficient muscle Jahnke, Vanessa E. Peterson, Jennifer M. Van Der Meulen, Jack H. Boehler, Jessica Uaesoontrachoon, Kitipong Johnston, Helen K. Defour, Aurelia Phadke, Aditi Yu, Qing Jaiswal, Jyoti K. Nagaraju, Kanneboyina Skelet Muscle Research BACKGROUND: Nonsense or loss-of-function mutations in the non-lysosomal cysteine protease calpain-3 result in limb-girdle muscular dystrophy type 2A (LGMD2A). While calpain-3 is implicated in muscle cell differentiation, sarcomere formation, and muscle cytoskeletal remodeling, the physiological basis for LGMD2A has remained elusive. METHODS: Cell growth, gene expression profiling, and mitochondrial content and function were analyzed using muscle and muscle cell cultures established from healthy and calpain-3-deficient mice. Calpain-3-deficient mice were also treated with PPAR-delta agonist (GW501516) to assess mitochondrial function and membrane repair. The unpaired t test was used to assess the significance of the differences observed between the two groups or treatments. ANOVAs were used to assess significance over time. RESULTS: We find that calpain-3 deficiency causes mitochondrial dysfunction in the muscles and myoblasts. Calpain-3-deficient myoblasts showed increased proliferation, and their gene expression profile showed aberrant mitochondrial biogenesis. Myotube gene expression analysis further revealed altered lipid metabolism in calpain-3-deficient muscle. Mitochondrial defects were validated in vitro and in vivo. We used GW501516 to improve mitochondrial biogenesis in vivo in 7-month-old calpain-3-deficient mice. This treatment improved satellite cell activity as indicated by increased MyoD and Pax7 mRNA expression. It also decreased muscle fatigability and reduced serum creatine kinase levels. The decreased mitochondrial function also impaired sarcolemmal repair in the calpain-3-deficient skeletal muscle. Improving mitochondrial activity by acute pyruvate treatment improved sarcolemmal repair. CONCLUSION: Our results provide evidence that calpain-3 deficiency in the skeletal muscle is associated with poor mitochondrial biogenesis and function resulting in poor sarcolemmal repair. Addressing this deficit by drugs that improve mitochondrial activity offers new therapeutic avenues for LGMD2A. BioMed Central 2020-12-11 /pmc/articles/PMC7730798/ /pubmed/33308300 http://dx.doi.org/10.1186/s13395-020-00254-1 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Jahnke, Vanessa E.
Peterson, Jennifer M.
Van Der Meulen, Jack H.
Boehler, Jessica
Uaesoontrachoon, Kitipong
Johnston, Helen K.
Defour, Aurelia
Phadke, Aditi
Yu, Qing
Jaiswal, Jyoti K.
Nagaraju, Kanneboyina
Mitochondrial dysfunction and consequences in calpain-3-deficient muscle
title Mitochondrial dysfunction and consequences in calpain-3-deficient muscle
title_full Mitochondrial dysfunction and consequences in calpain-3-deficient muscle
title_fullStr Mitochondrial dysfunction and consequences in calpain-3-deficient muscle
title_full_unstemmed Mitochondrial dysfunction and consequences in calpain-3-deficient muscle
title_short Mitochondrial dysfunction and consequences in calpain-3-deficient muscle
title_sort mitochondrial dysfunction and consequences in calpain-3-deficient muscle
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730798/
https://www.ncbi.nlm.nih.gov/pubmed/33308300
http://dx.doi.org/10.1186/s13395-020-00254-1
work_keys_str_mv AT jahnkevanessae mitochondrialdysfunctionandconsequencesincalpain3deficientmuscle
AT petersonjenniferm mitochondrialdysfunctionandconsequencesincalpain3deficientmuscle
AT vandermeulenjackh mitochondrialdysfunctionandconsequencesincalpain3deficientmuscle
AT boehlerjessica mitochondrialdysfunctionandconsequencesincalpain3deficientmuscle
AT uaesoontrachoonkitipong mitochondrialdysfunctionandconsequencesincalpain3deficientmuscle
AT johnstonhelenk mitochondrialdysfunctionandconsequencesincalpain3deficientmuscle
AT defouraurelia mitochondrialdysfunctionandconsequencesincalpain3deficientmuscle
AT phadkeaditi mitochondrialdysfunctionandconsequencesincalpain3deficientmuscle
AT yuqing mitochondrialdysfunctionandconsequencesincalpain3deficientmuscle
AT jaiswaljyotik mitochondrialdysfunctionandconsequencesincalpain3deficientmuscle
AT nagarajukanneboyina mitochondrialdysfunctionandconsequencesincalpain3deficientmuscle