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Lysosomal Function Impacts the Skeletal Muscle Extracellular Matrix
Muscle development and homeostasis are critical for normal muscle function. A key aspect of muscle physiology during development, growth, and homeostasis is modulation of protein turnover, the balance between synthesis and degradation of muscle proteins. Protein degradation depends upon lysosomal pH...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8629007/ https://www.ncbi.nlm.nih.gov/pubmed/34842731 http://dx.doi.org/10.3390/jdb9040052 |
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author | Coffey, Elizabeth C. Astumian, Mary Alrowaished, Sarah S. Schaffer, Claire Henry, Clarissa A. |
author_facet | Coffey, Elizabeth C. Astumian, Mary Alrowaished, Sarah S. Schaffer, Claire Henry, Clarissa A. |
author_sort | Coffey, Elizabeth C. |
collection | PubMed |
description | Muscle development and homeostasis are critical for normal muscle function. A key aspect of muscle physiology during development, growth, and homeostasis is modulation of protein turnover, the balance between synthesis and degradation of muscle proteins. Protein degradation depends upon lysosomal pH, generated and maintained by proton pumps. Sphingolipid transporter 1 (spns1), a highly conserved gene encoding a putative late endosome/lysosome carbohydrate/H(+) symporter, plays a pivotal role in maintaining optimal lysosomal pH and spns1(−/−) mutants undergo premature senescence. However, the impact of dysregulated lysosomal pH on muscle development and homeostasis is not well understood. We found that muscle development proceeds normally in spns1(−/−) mutants prior to the onset of muscle degeneration. Dysregulation of the extracellular matrix (ECM) at the myotendinous junction (MTJ) coincided with the onset of muscle degeneration in spns1(−/−) mutants. Expression of the ECM proteins laminin 111 and MMP-9 was upregulated. Upregulation of laminin 111 mitigated the severity of muscle degeneration, as inhibition of adhesion to laminin 111 exacerbated muscle degeneration in spns1(−/−) mutants. MMP-9 upregulation was induced by tnfsf12 signaling, but abrogation of MMP-9 did not impact muscle degeneration in spns1(−/−) mutants. Taken together, these data indicate that dysregulated lysosomal pH impacts expression of ECM proteins at the myotendinous junction. |
format | Online Article Text |
id | pubmed-8629007 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-86290072021-11-30 Lysosomal Function Impacts the Skeletal Muscle Extracellular Matrix Coffey, Elizabeth C. Astumian, Mary Alrowaished, Sarah S. Schaffer, Claire Henry, Clarissa A. J Dev Biol Article Muscle development and homeostasis are critical for normal muscle function. A key aspect of muscle physiology during development, growth, and homeostasis is modulation of protein turnover, the balance between synthesis and degradation of muscle proteins. Protein degradation depends upon lysosomal pH, generated and maintained by proton pumps. Sphingolipid transporter 1 (spns1), a highly conserved gene encoding a putative late endosome/lysosome carbohydrate/H(+) symporter, plays a pivotal role in maintaining optimal lysosomal pH and spns1(−/−) mutants undergo premature senescence. However, the impact of dysregulated lysosomal pH on muscle development and homeostasis is not well understood. We found that muscle development proceeds normally in spns1(−/−) mutants prior to the onset of muscle degeneration. Dysregulation of the extracellular matrix (ECM) at the myotendinous junction (MTJ) coincided with the onset of muscle degeneration in spns1(−/−) mutants. Expression of the ECM proteins laminin 111 and MMP-9 was upregulated. Upregulation of laminin 111 mitigated the severity of muscle degeneration, as inhibition of adhesion to laminin 111 exacerbated muscle degeneration in spns1(−/−) mutants. MMP-9 upregulation was induced by tnfsf12 signaling, but abrogation of MMP-9 did not impact muscle degeneration in spns1(−/−) mutants. Taken together, these data indicate that dysregulated lysosomal pH impacts expression of ECM proteins at the myotendinous junction. MDPI 2021-11-23 /pmc/articles/PMC8629007/ /pubmed/34842731 http://dx.doi.org/10.3390/jdb9040052 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Coffey, Elizabeth C. Astumian, Mary Alrowaished, Sarah S. Schaffer, Claire Henry, Clarissa A. Lysosomal Function Impacts the Skeletal Muscle Extracellular Matrix |
title | Lysosomal Function Impacts the Skeletal Muscle Extracellular Matrix |
title_full | Lysosomal Function Impacts the Skeletal Muscle Extracellular Matrix |
title_fullStr | Lysosomal Function Impacts the Skeletal Muscle Extracellular Matrix |
title_full_unstemmed | Lysosomal Function Impacts the Skeletal Muscle Extracellular Matrix |
title_short | Lysosomal Function Impacts the Skeletal Muscle Extracellular Matrix |
title_sort | lysosomal function impacts the skeletal muscle extracellular matrix |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8629007/ https://www.ncbi.nlm.nih.gov/pubmed/34842731 http://dx.doi.org/10.3390/jdb9040052 |
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