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Exercise alleviates cognitive dysfunction in Alzheimer’s disease mice via skeletal muscle-derived extracellular vesicles which enhance plaque clearance by microglia [RNA-Seq]

ABSTRACT: Exercise confers cognitive benefits in Alzheimer’s disease (AD), yet the underlying mechanisms remain incompletely understood. The skeletal muscle functions as an endocrine organ that secretes myokines which affect the homeostasis of extra-muscular organs, including the brain. Here, we found that swimming exercises promoted the secretion of skeletal muscle-derived extracellular vesicles (SKM-EVs), which subsequently pinocytosis by microglia. Gain- and loss-of-function experiments showed that exercised SKM-EVs activated the polarization of disease-associated microglia (DAM) and enhanced the clearance of amyloid-beta (Aβ) plaques. Furthermore, miR-378a-3p was identified as the key miRNA in SKM-EVs and promoted lipid metabolism in DAM by targeting p110α. Importantly, the therapeutic administration of EVs derived from mir-378a overexpressing myotubes alleviated cognitive impairment in AD mice. Together, our findings demonstrate that exercised SKM-EVs could serve as a novel myokine mediating communication from skeletal muscle to the brain and develop alternative therapeutic strategies for exercise in AD treatment.

ORGANISM(S): Mus musculus

PROVIDER: GSE313455 | GEO | 2025/12/18

REPOSITORIES: GEO

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Project description:The adult skeletal muscle is a plastic tissue with a remarkable ability to adapt to different levels of activity by altering its excitability, its contractile and metabolic phenotype and its mass. Knowledge on the mechanisms responsible for muscle mass comes primarily from models of muscle inactivity or denervation or from genetic models of muscle diseases. Given that the underlying exercise-induced transcriptional mechanisms regulating muscle mass are not fully understood, here we investigated the cellular and molecular adaptive mechanisms taking place in fast skeletal muscle of adult zebrafish in response to swimming. Fish were trained at low swimming speed (0.1 m/s; non-exercised) or at their optimal swimming speed (0.4 m/s; exercised). A significant increase in fibre cross-sectional area (1,290 M-BM-1 88 vs. 1,665 M-BM-1 106 M-NM-<m2) and vascularization (298 M-BM-1 23 vs. 458 M-BM-1 38 capillaries/mm2) was found in exercised over non-exercised fish. Gene expression profiling evidenced the transcriptional activation of a series of complex networks of extracellular and intracellular signaling molecules and pathways involved in the regulation of muscle mass, myogenesis and angiogenesis, many (e.g. BMP, TGFM-oM-^AM-", FGF, Notch, Wnt, MEF2, Shh, EphrinB2) not previously associated with exercise-induced contractile activity, and that recapitulate in part the transcriptional events occurring during skeletal muscle regeneration. These results demonstrate that fibre hypertrophy is responsible for the growth-promoting effects of exercise accompanied by a switch to a more oxidative capacity of white muscle fibres to fuel the increased energy demands. Importantly, our study identified novel molecular mechanisms regulating muscle mass and function in vertebrates. Adult zebrafish were subjected or not to a swim training regime consisting of swimming at the optimal swimming speed for this species for 6 h/day, 5 days/week for a total of 4 weeks (20 experimental days). Total RNA of fast muscle from individual non-exercised (n = 8) and exercised (n = 8) zebrafish was analyzed.

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Exercise alleviates cognitive dysfunction in Alzheimer’s disease mice via skeletal muscle-derived extracellular vesicles which enhance plaque clearance by microglia [RNA-Seq]

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