Dataset Information

Sarcosine decreases in sarcopenia and enhances muscle regeneration and adipose thermogenesis by activating ant-inflammatory macrophages (cohort2)

ABSTRACT:

Age-related changes in circulating metabolites significantly influence systemic physiology and may contribute to diseases like sarcopenia. Although metabolic dysregulation is closely linked to sarcopenia, the roles of specific metabolites remain unclear. Here we performed comprehensive plasma metabolomic and lipidomic analyses across two cohorts comprising 1,013 individuals. Our findings revealed the metabolic characteristics of sarcopenia, including a notable decline in plasma sarcosine levels in both aging and sarcopenic individuals. Functional studies showed that sarcosine helps maintain muscle mass homeostasis during aging, promotes adipose thermogenesis and enhances muscle regeneration. These effects may increase energy expenditure and restore metabolic balance to reduce chronic inflammation and improve insulin sensitivity, which are crucial for managing sarcopenia. We demonstrate that sarcosine activated the GCN2 signaling pathway to enhance anti-inflammatory macrophage polarization, promoting adipose thermogenesis and muscle regeneration. This study underscores the potential of sarcosine supplementation as an adjunctive strategy for preventing sarcopenia in older adults.

cohort2 is reported in the current study MTBLS12036.

cohort1 is reported in MTBLS12015.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - positive - hilic, Liquid Chromatography MS - - reverse phase

PROVIDER: MTBLS12036 | MetaboLights | 2025-05-06

REPOSITORIES: MetaboLights

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			Action	DRS
	LPH2012-088-1ul-pos-1008.raw	Raw
	LPH2012-088-1ul-pos-130.raw	Raw
	LPH2012-088-1ul-pos-143.raw	Raw
	LPH2012-088-1ul-pos-153.raw	Raw
	LPH2012-088-1ul-pos-168.raw	Raw

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Project description:The degenerative loss of muscle associated with aging leading to muscular atrophy is called sarcopenia. Currently, practicing regular physical exercise is the only efficient way to delay the onset of sarcopenia. To identify therapeutic targets to suppress the symptoms of aging, there is a need for in vivo model organisms of accelerated muscle degeneration and atrophy. The zebrafish harbors hallmarks of aging, notably mitochondrial dysfunction, telomeres shortening and accumulation of senescent cells. Unfortunately, zebrafish aged slowly, and no specific zebrafish models of accelerated muscle atrophy associated with aging or sarcopenia are currently available. We have developed a new genetic tool to efficiently accelerate muscle fibers degeneration and muscle tissue atrophy in zebrafish larvae and adults. We used a gain-of-function strategy with a molecule that has been shown to be necessary and sufficient to induce muscle atrophy and a sarcopenia phenotype in mammals: Atrogin1 (also named Fbxo32). We report the generation, validation, and characterization of a zebrafish genetic model of accelerated muscle atrophy, the sarcofish. We demonstrated that specific expression of Atrogin1 in skeletal muscle tissue induces a muscle atrophic phenotype associated with locomotion dysfunctions in both larvae and adult fish. We identified that degradation of the myosin light chain as an event occurring before the degeneration of muscle fibers. Biological processes associated with muscle aging such as inflammation, proteolysis, apoptosis and stress response are upregulated in the sarcofish. Surprisingly, we observed a strong correlation between muscle fibers degeneration and a reduction of neuromuscular junctions in the peripheral nervous system, as well as neuronal cell bodies in the spinal cord, suggesting that muscle atrophy could underly a neurodegenerative phenotype in the central nervous system. Finally, while sarcofish larvae harbor regeneration of muscle fibers, spinal neurons and recover locomotive functions, adult sarcofish have impaired regenerative capacities as observed in mammals during muscle aging. In the future, the sarcofish could open new strategies in the fight against the sarcopenia disease to test therapeutic molecules aiming to treat or alleviate the symptoms of muscle aging.

Project description:Aims: Sarcopenia is the degenerative loss of skeletal muscle mass and function at high age, which affects 5-13% of people aged 60-70 years. Although a number of factors have been linked to sarcopenia, it remains unclear what determines its emergence in some but not all individuals and there are no medical treatments available. Mice and rats are widely used as model organisms to identify factors predisposing to sarcopenia, but the extent to which age-related molecular changes in wild-type mice and rats recapitulate those occurring in humans is not known. The aim of this project was to define a conserved set of regulators of aging-related reduction in muscle function that could be targeted by future therapies. Methods: We comparatively analyzed phenotypic parameters as well as the transcriptomes of the Gastrocnemius muscle from mice, rats and humans of a wide range of ages. We further inferred computationally the transcription regulators that likely underlie the molecular changes associated with aging-related loss in muscle functionality. Results: The analysis showed that the biological age of rodents that muscle mass is a better indicator of muscle functionality than the chronological age. Investigating the molecular changes associated with the aging-related loss of muscle mass, we discovered changes in gene expression that are shared between the studied species at the level of molecular pathways rather than at the level of individual genes. Beyond the known involvement of inflammation and mitochondrial function in aging, we found that the transcription regulators SPIB, ESRRB and YY1/YY2 consistently underlie aging-related molecular changes across the studied species. Conclusions: Rodents recapitulate well the molecular changes observed in human sarcopenia, but the conservation is stronger at the molecular pathway level than at the level of individual genes. Phenotypic parameters such as the muscle mass should be taken into account in stratifying samples for analyzing aging-related processes, as the chronological age is a poorer indicator of organ functionality. The shared regulators of aging-related muscle loss that we identified here can be studied further in rodent models of sarcopenia toward defining new targets for therapy in humans.

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Sarcosine decreases in sarcopenia and enhances muscle regeneration and adipose thermogenesis by activating ant-inflammatory macrophages (cohort2)

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