Cargando…
Skeletal Muscle Modulates Huntington’s Disease Pathogenesis in Mice: Role of Physical Exercise
Huntington’s disease (HD) is a monogenic fatal neurodegenerative disorder. However, there is increasing evidence that HD is a pleiotropic systemic disorder. In particular, skeletal muscle metabolism is greatly affected in HD, which in turn can have a major impact on whole-body metabolism and energet...
Autores principales: | , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
SAGE Publications
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6210627/ https://www.ncbi.nlm.nih.gov/pubmed/30397387 http://dx.doi.org/10.1177/1179069518809059 |
_version_ | 1783367159289741312 |
---|---|
author | Corrochano, Silvia Blanco, Gonzalo Acevedo-Arozena, Abraham |
author_facet | Corrochano, Silvia Blanco, Gonzalo Acevedo-Arozena, Abraham |
author_sort | Corrochano, Silvia |
collection | PubMed |
description | Huntington’s disease (HD) is a monogenic fatal neurodegenerative disorder. However, there is increasing evidence that HD is a pleiotropic systemic disorder. In particular, skeletal muscle metabolism is greatly affected in HD, which in turn can have a major impact on whole-body metabolism and energetic balance. Throughout an unbiased mutagenesis approach in HD mice, we have found that Scn4a, a skeletal muscle–specific sodium channel gene, is a modifier of the disease. Mutations in Scn4a enhance HD disease progression and weight loss by accelerating muscle waste and cachexia, increasing skeletal muscle activity and energy demands. At the molecular level, Scn4a mutations activate AMP-activated protein kinase (AMPK), leading to a fibre switch towards more oxidative types. These adaptations seen in HD; Scn4a double mutant muscles are similar to those observed in healthy individuals after endurance exercise training regimes. This prompted us to assess the effects of an endurance exercise regime in HD mice, independently showing that skeletal muscle adaptations leading to the activation of AMPK are detrimental for HD pathogenesis. Although it is undeniable that physical exercise can lead to many health benefits, our work shows that, at least under certain situations such as in HD, an endurance exercise routine could be a detrimental therapeutic option. |
format | Online Article Text |
id | pubmed-6210627 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | SAGE Publications |
record_format | MEDLINE/PubMed |
spelling | pubmed-62106272018-11-05 Skeletal Muscle Modulates Huntington’s Disease Pathogenesis in Mice: Role of Physical Exercise Corrochano, Silvia Blanco, Gonzalo Acevedo-Arozena, Abraham J Exp Neurosci Commentary Huntington’s disease (HD) is a monogenic fatal neurodegenerative disorder. However, there is increasing evidence that HD is a pleiotropic systemic disorder. In particular, skeletal muscle metabolism is greatly affected in HD, which in turn can have a major impact on whole-body metabolism and energetic balance. Throughout an unbiased mutagenesis approach in HD mice, we have found that Scn4a, a skeletal muscle–specific sodium channel gene, is a modifier of the disease. Mutations in Scn4a enhance HD disease progression and weight loss by accelerating muscle waste and cachexia, increasing skeletal muscle activity and energy demands. At the molecular level, Scn4a mutations activate AMP-activated protein kinase (AMPK), leading to a fibre switch towards more oxidative types. These adaptations seen in HD; Scn4a double mutant muscles are similar to those observed in healthy individuals after endurance exercise training regimes. This prompted us to assess the effects of an endurance exercise regime in HD mice, independently showing that skeletal muscle adaptations leading to the activation of AMPK are detrimental for HD pathogenesis. Although it is undeniable that physical exercise can lead to many health benefits, our work shows that, at least under certain situations such as in HD, an endurance exercise routine could be a detrimental therapeutic option. SAGE Publications 2018-10-30 /pmc/articles/PMC6210627/ /pubmed/30397387 http://dx.doi.org/10.1177/1179069518809059 Text en © The Author(s) 2018 http://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the Creative Commons Attribution 4.0 License (http://www.creativecommons.org/licenses/by/4.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). |
spellingShingle | Commentary Corrochano, Silvia Blanco, Gonzalo Acevedo-Arozena, Abraham Skeletal Muscle Modulates Huntington’s Disease Pathogenesis in Mice: Role of Physical Exercise |
title | Skeletal Muscle Modulates Huntington’s Disease Pathogenesis in Mice: Role of Physical Exercise |
title_full | Skeletal Muscle Modulates Huntington’s Disease Pathogenesis in Mice: Role of Physical Exercise |
title_fullStr | Skeletal Muscle Modulates Huntington’s Disease Pathogenesis in Mice: Role of Physical Exercise |
title_full_unstemmed | Skeletal Muscle Modulates Huntington’s Disease Pathogenesis in Mice: Role of Physical Exercise |
title_short | Skeletal Muscle Modulates Huntington’s Disease Pathogenesis in Mice: Role of Physical Exercise |
title_sort | skeletal muscle modulates huntington’s disease pathogenesis in mice: role of physical exercise |
topic | Commentary |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6210627/ https://www.ncbi.nlm.nih.gov/pubmed/30397387 http://dx.doi.org/10.1177/1179069518809059 |
work_keys_str_mv | AT corrochanosilvia skeletalmusclemodulateshuntingtonsdiseasepathogenesisinmiceroleofphysicalexercise AT blancogonzalo skeletalmusclemodulateshuntingtonsdiseasepathogenesisinmiceroleofphysicalexercise AT acevedoarozenaabraham skeletalmusclemodulateshuntingtonsdiseasepathogenesisinmiceroleofphysicalexercise |