Aquaporin‐4 Orchestrates Muscle Cell Differentiation and Satellite Cell Preservation: A Novel Target in Age‐Related Muscle Decline
4 affiliations
- 1Department of Biochemistry and Molecular Biology II, School of Pharmacy University of Granada Granada Spain
- 2Abbott Nutrition R&D Abbott Laboratories Granada Spain
- 3Abbott Nutrition R&D Abbott Laboratories Columbus Ohio USA
- 4Department de Bioquimica I Biologia Molecular, Facultat de Biologia Universitat de Barcelona Barcelona Spain
Abstract
Background: Impaired muscle regeneration is a key contributor to age‐related muscle decline, yet the molecular mechanisms linking muscle water homeostasis to regenerative failure remain incompletely understood. Aquaporin‐4 (AQP4), a major skeletal muscle water channel, may have functions beyond water transport that are relevant to muscle maintenance and repair. We investigated whether altered AQP4 expression contributes to age‐related defects in skeletal muscle regeneration and whether AQP4 may represent a targetable pathway for muscle dysfunction associated with ageing.
Methods: Skeletal muscle from young adult (25‐week; n = 9) and aged (85‐week; n = 8) rats was analysed for extracellular and intracellular water content by bioimpedance. AQP4, AQP1 and myogenic markers were measured by Western blot. Satellite cells isolated from skeletal muscle were assessed for proliferation, differentiation and expression of differentiation markers. To define the mechanistic role of AQP4 in myogenesis, CRISPR‐generated AQP4‐silenced L6 rat myoblasts were evaluated for proliferation, differentiation, senescence and Akt/PKB signalling. Rescue experiments were performed by restoring AQP4 expression in silenced cells. Data are reported as mean ± SEM.
Results: Compared with young rats, aged rats showed an altered intracellular water‐to‐lean mass ratio (0.94 vs. 0.62, p < 0.05), a 33% reduction in AQP4 expression (p < 0.05) and reduced muscle strength (3.1 vs. 2.6, p < 0.05), with AQP4 levels correlating with muscle performance. Satellite cells from aged muscle exhibited 29% lower AQP4 expression and 39% lower Pax7 expression (both p < 0.05), together with reduced myogenic differentiation (30% decrease, p < 0.05). In L6 myoblasts, AQP4 silencing reduced proliferation (20% decrease, p < 0.05), impaired myotube differentiation (50% decrease, p < 0.05), increased senescence (30% increase, p < 0.05) and decreased Akt/PKB signalling by 42% (p < 0.05). AQP4 silencing was also associated with decreased dystrophin localization at the plasma membrane (50%, p < 0.05). Re‐expression of AQP4 reversed these abnormalities and restored the phenotype toward wild‐type levels (all p < 0.05).
Conclusions: Reduced AQP4 expression is associated with impaired muscle regeneration and functional decline in aged skeletal muscle. Experimental AQP4 loss disrupts myogenic signalling, membrane organization and increases progression to senescence, whereas AQP4 restoration rescues these defects. These findings identify AQP4 as a biologically plausible therapeutic target for strategies aimed at preserving or restoring muscle health and regenerative capacity in ageing‐associated muscle dysfunction.
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BibTeX
@article{giron2026aquaporin4,
title = {{Aquaporin‐4 Orchestrates Muscle Cell Differentiation and Satellite Cell Preservation: A Novel Target in Age‐Related Muscle Decline}},
author = {María D. Girón and Manuel Manzano and Suzette L. Pereira and Antonio Reinoso and Chiara Burgio and Nora Montero‐Martin and Guillermo Jiménez‐Jiménez and Josep M. Argilés and Ricardo Rueda and José M. López‐Pedrosa and Rafael Salto},
journal = {Journal of Cachexia, Sarcopenia and Muscle},
year = {2026},
month = oct,
doi = {10.1002/jcsm.70412},
url = {https://doi.org/10.1002/jcsm.70412},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Aquaporin‐4 Orchestrates Muscle Cell Differentiation and Satellite Cell Preservation: A Novel Target in Age‐Related Muscle Decline
AU - María D. Girón
AU - Manuel Manzano
AU - Suzette L. Pereira
AU - Antonio Reinoso
AU - Chiara Burgio
AU - Nora Montero‐Martin
AU - Guillermo Jiménez‐Jiménez
AU - Josep M. Argilés
AU - Ricardo Rueda
AU - José M. López‐Pedrosa
AU - Rafael Salto
PY - 2026
DA - 2026/10/27
JO - Journal of Cachexia, Sarcopenia and Muscle
DO - 10.1002/jcsm.70412
UR - https://doi.org/10.1002/jcsm.70412
AB - Background: Impaired muscle regeneration is a key contributor to age‐related muscle decline, yet the molecular mechanisms linking muscle water homeostasis to regenerative failure remain incompletely understood. Aquaporin‐4 (AQP4), a major skeletal muscle water channel, may have functions beyond water transport that are relevant to muscle maintenance and repair. We investigated whether altered AQP4 expression contributes to age‐related defects in skeletal muscle regeneration and whether AQP4 may represent a targetable pathway for muscle dysfunction associated with ageing. Methods: Skeletal muscle from young adult (25‐week; n = 9) and aged (85‐week; n = 8) rats was analysed for extracellular and intracellular water content by bioimpedance. AQP4, AQP1 and myogenic markers were measured by Western blot. Satellite cells isolated from skeletal muscle were assessed for proliferation, differentiation and expression of differentiation markers. To define the mechanistic role of AQP4 in myogenesis, CRISPR‐generated AQP4‐silenced L6 rat myoblasts were evaluated for proliferation, differentiation, senescence and Akt/PKB signalling. Rescue experiments were performed by restoring AQP4 expression in silenced cells. Data are reported as mean ± SEM. Results: Compared with young rats, aged rats showed an altered intracellular water‐to‐lean mass ratio (0.94 vs. 0.62, p < 0.05), a 33% reduction in AQP4 expression (p < 0.05) and reduced muscle strength (3.1 vs. 2.6, p < 0.05), with AQP4 levels correlating with muscle performance. Satellite cells from aged muscle exhibited 29% lower AQP4 expression and 39% lower Pax7 expression (both p < 0.05), together with reduced myogenic differentiation (30% decrease, p < 0.05). In L6 myoblasts, AQP4 silencing reduced proliferation (20% decrease, p < 0.05), impaired myotube differentiation (50% decrease, p < 0.05), increased senescence (30% increase, p < 0.05) and decreased Akt/PKB signalling by 42% (p < 0.05). AQP4 silencing was also associated with decreased dystrophin localization at the plasma membrane (50%, p < 0.05). Re‐expression of AQP4 reversed these abnormalities and restored the phenotype toward wild‐type levels (all p < 0.05). Conclusions: Reduced AQP4 expression is associated with impaired muscle regeneration and functional decline in aged skeletal muscle. Experimental AQP4 loss disrupts myogenic signalling, membrane organization and increases progression to senescence, whereas AQP4 restoration rescues these defects. These findings identify AQP4 as a biologically plausible therapeutic target for strategies aimed at preserving or restoring muscle health and regenerative capacity in ageing‐associated muscle dysfunction.
SN - 2190-5991
SN - 2190-6009
ER -