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Mechanosensors control skeletal muscle mass, molecular clocks, and metabolism

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Abstract

Background

Skeletal muscles (SkM) are mechanosensitive, with mechanical unloading resulting in muscle-devastating conditions and altered metabolic properties. However, it remains unexplored whether these atrophic conditions affect SkM mechanosensors and molecular clocks, both crucial for their homeostasis and consequent physiological metabolism.

Methods

We induced SkM atrophy through 14 days of hindlimb suspension (HS) in 10 male C57BL/6J mice and 10 controls (CTR). SkM histology, gene expressions and protein levels of mechanosensors, molecular clocks and metabolism-related players were examined in the m. Gastrocnemius and m. Soleus. Furthermore, we genetically reduced the expression of mechanosensors integrin-linked kinase (Ilk1) and kindlin-2 (Fermt2) in myogenic C2C12 cells and analyzed the gene expression of mechanosensors, clock components and metabolism-controlling genes.

Results

Upon hindlimb suspension, gene expression levels of both core molecular clocks and mechanosensors were moderately upregulated in m. Gastrocnemius but strongly downregulated in m. Soleus. Upon unloading, metabolism- and protein biosynthesis-related genes were moderately upregulated in m. Gastrocnemius but downregulated in m. Soleus. Furthermore, we identified very strong correlations between mechanosensors, metabolism- and circadian clock-regulating genes. Finally, genetically induced downregulations of mechanosensors Ilk1 and Fermt2 caused a downregulated mechanosensor, molecular clock and metabolism-related gene expression in the C2C12 model.

Conclusions

Collectively, these data shed new lights on mechanisms that control muscle loss. Mechanosensors are identified to crucially control these processes, specifically through commanding molecular clock components and metabolism.

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Data availability

The data will be made available from the corresponding author upon reasonable request.

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Acknowledgements

The authors would like to thank Monique Ramaekers for technical assistance during the tissue collections.

Funding

Mathias Vanmunster is a recipient of an FWO Fundamental Research PhD scholarship (Project Number 1186720N). Sebastiaan Dalle has received a postdoctoral fellowship (12Z8622N) from Research Foundation Flanders (FWO). The project was funded by a KU Leuven grant (Project Number C14/19/092) as well as an FWO grant (Project Number: G056521N) to Frank Suhr.

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Authors and Affiliations

  1. Department of Movement Sciences, Exercise Physiology Research Group, KU Leuven, 3001, Leuven, Belgium

    Mathias Vanmunster, Ana Victoria Rojo Garcia, Alexander Pacolet, Sebastiaan Dalle, Katrien Koppo & Frank Suhr

  2. Department of Movement Sciences, Human Movement Biomechanics Research Group, KU Leuven, 3001, Leuven, Belgium

    Ilse Jonkers

  3. Department of Development and Regeneration, Skeletal Biology and Engineering Research Center, KU Leuven, 3000, Leuven, Belgium

    Rik Lories

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  1. Mathias Vanmunster
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  2. Ana Victoria Rojo Garcia
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  8. Frank Suhr
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Contributions

Project design: FS; Performing experiments: MV, AVRG, AP, SD; Data analysis: FS, MV; Provided reagents: FS, KK; Drafting the manuscript: FS, MV; Final approval of the manuscript: MV, AVRG, AP, SD, KK, FS.

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Correspondence to Frank Suhr.

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Vanmunster, M., Rojo Garcia, A.V., Pacolet, A. et al. Mechanosensors control skeletal muscle mass, molecular clocks, and metabolism. Cell. Mol. Life Sci. 79, 321 (2022). https://doi.org/10.1007/s00018-022-04346-7

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  • DOI: https://doi.org/10.1007/s00018-022-04346-7

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