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Restoring Systemic GDF11 Levels Reverses Age-Related Dysfunction in Mouse Skeletal Muscle

ABSTRACT: In this study, we investigated signaling pathways in Skeletal muscle precursors that are altered with aging and age-related deficits in muscle regenerative potential. We performed fluorescence activated cell sorting (FACS) to obtain highly purified skeletal muscle satellite cells from young, middle-aged and old mice. Parabiosis experiments indicate that impaired regeneration in aged mice is reversible by exposure to a young circulation, suggesting that young blood contains humoral "rejuvenating" factors that can restore regenerative function. Here, we demonstrate that the circulating protein growth differentiation factor 11 (GDF11) is a rejuvenating factor for skeletal muscle. Supplementation of systemic GDF11 levels, which normally decline with age, by heterochronic parabiosis or systemic delivery of recombinant protein, reversed functional impairments and restored genomic integrity in aged muscle stem cells (satellite cells). Increased GDF11 levels in aged mice also improved muscle structural and functional features and increased strength and endurance exercise capacity. These data indicate that GDF11 systemically regulates muscle aging and may be therapeutically useful for reversing age-related skeletal muscle and stem cell dysfunction.

ORGANISM(S): Mus musculus

PROVIDER: GSE50821 | GEO | 2014/05/08

SECONDARY ACCESSION(S): PRJNA219090

REPOSITORIES: GEO

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Restoring Systemic GDF11 Levels Reverses Age-Related Dysfunction in Mouse Skeletal Muscle

Project description:In this study, we investigated signaling pathways in Skeletal muscle precursors that are altered with aging and age-related deficits in muscle regenerative potential. We performed fluorescence activated cell sorting (FACS) to obtain highly purified skeletal muscle satellite cells from young, middle-aged and old mice. Parabiosis experiments indicate that impaired regeneration in aged mice is reversible by exposure to a young circulation, suggesting that young blood contains humoral "rejuvenating" factors that can restore regenerative function. Here, we demonstrate that the circulating protein growth differentiation factor 11 (GDF11) is a rejuvenating factor for skeletal muscle. Supplementation of systemic GDF11 levels, which normally decline with age, by heterochronic parabiosis or systemic delivery of recombinant protein, reversed functional impairments and restored genomic integrity in aged muscle stem cells (satellite cells). Increased GDF11 levels in aged mice also improved muscle structural and functional features and increased strength and endurance exercise capacity. These data indicate that GDF11 systemically regulates muscle aging and may be therapeutically useful for reversing age-related skeletal muscle and stem cell dysfunction. We used Affymetrix Mouse Genome array to identify global transcriptional changes associated with age in skeletal muscle precursors.

2014-05-08 | E-GEOD-50821 | biostudies-arrayexpress

Expression data from skeletal muscle satellite cells at different development stages

Project description:Satellite cells are responsible for the long-term regenerative capacity of adult skeletal muscle. The diminished muscle performance and regenerative capacity of aged muscle is thought to reflect progressive fibrosis and atrophy. Whether this reduction in muscle competency also involves a diminishment in the intrinsic regulation of satellite cell self-renewal remains unknown. We used microarray to identify gene expression changes underlying the marked reduction in the capacity of satellite cells to self-renew, contribute to regeneration and repopulate the niche as they age. Skeletal muscles from heterozygous Pax7-ZsGreen mice were isolated at defined stages: E17.5 (fetal - whole forelimb and hindlimb), postnatal day 21 (adolescent - hindlimb), 2-3 month old (young adult - hindlimb) and >1 year old (older adult - hindlimb) mice. ZsGreen-positive skeletal muscle satellite cells were isolated by FACS and pooled (fetal n=4, adolescent n=6, young adult n=8 and older adult n=8 mice).

2014-05-26 | E-GEOD-47401 | biostudies-arrayexpress

Small extracellular vesicles from young plasma reverse age-related functional declines by improving mitochondrial energy metabolism

Project description:Aging and the chronic diseases associated with aging have become a great burden to modern society. Recent animal studies on heterochronic parabiosis have revealed that young blood has a powerful rejuvenating effect on aged tissues, but which components of the young blood are responsible for the rejuvenating effects remains unclear. In this study, we found that small extracellular vesicles (sEVs) purified from the plasma of young mice could counteract pre-existing aging at the molecular, mitochondrial, cellular and physiological levels. In detail, injection of young sEVs into aged mice extended lifespan, attenuated senescent phenotypes and mitigate age-associated impairments on various tissues (hippocampus, muscle, heart, testis, bone, etc). Mechanistical studies using iTRAQ-based quantitative proteomic analyses combined with GO term cluster revealed that the altered proteomes in aged tissues of young sEVs-treated mice were specifically related to their roles in regulating cellular senescence, metabolic process, epigenetic modification, genomic stability, etc, which are the cardinal features associated with aging. Particularly, the sEVs derived from young mice and young human donors could stimulate PGC-1α (a master regulator of mitochondrial biogenesis and energy metabolism) expression in vitro and in vivo through their rejuvenating miRNA cargos, thereby facilitating mitochondrial regeneration and counteracting mitochondrial deficits in aged tissues. Taken together, this study demonstrates that young sEVs can reverse degenerative changes and age-related dysfunctions through stimulating PGC-1α expression and regenerating intact mitochondria.

2024-03-31 | PXD030350 | Pride

P38 signaling underlies a cell-autonomous loss of stem cell self-renewal in aged muscle

Project description:Skeletal muscle aging results in a gradual loss of skeletal muscle mass, skeletal muscle function and decreased regenerative capacity, which can lead to sarcopenia and increased mortality. While the mechanisms underlying sarcopenia remain unclear, the skeletal muscle stem cell, or satellite cell, is required for muscle regeneration. Therefore, identification of signaling pathways affecting satellite cell function during aging may provide insights into therapeutic targets for combating sarcopenia. Here, we show that a cell-autonomous loss in self-renewal occurs via novel alterations in FGF and p38αβ MAPK signaling in old satellite cells. We further demonstrate that pharmacological manipulation of these pathways can ameliorate age-associated self-renewal defects. Thus, our data highlight an age-associated deregulation of a satellite cell homeostatic network and reveals potential therapeutic opportunities for the treatment of progressive muscle wasting. Satellite cells were isolated from young (3-6mo) and aged (20-25mo) adult mice; individual date files represent 2 independent pools of RNA from 4-8 mice at each timepoint.

2013-09-01 | E-GEOD-47104 | biostudies-arrayexpress

Profiling of mouse muscle stem cells aging and activation upon skeletal muscle injury

Project description:Utilizing glycerol intramuscular injections in M. musculus provide a models of skeletal muscle damage followed by skeletal muscle regeneration. In particular, glycerol-induced muscle injury triggers accute activation of skeletal muscle stem cells, called satellite cells. However, aging dramatically impairs the regenerative capacity of satellite cells. We characterized genome-wide expression profiles of young and old satellite cells in the non-proliferative and activated state, freshly isolated to non-injured or damaged muscles, respectively. Our goal was to uncover new regulatory signaling specific to satellite cells entry into the activation and myogenic program that are affected with age. Satellite cells were isolated in either quiescent / non-proliferative or activated state from uninjured or 3 days after glycerol-induced injury of tibialis anterior, gastrocnemius and quadriceps, respectively. Young (2-4 months old) and old (20-24 months old) wildtype C57BL/6J male were used, with five to six biological replicates per group.

2016-07-04 | E-GEOD-81096 | biostudies-arrayexpress

Expression data from skeletal muscle satellite cells at different development stages

2014-05-26 | GSE47401 | GEO

Profiling of mouse muscle stem cells aging and activation upon skeletal muscle injury

2016-07-04 | GSE81096 | GEO

Impaired phagocytic function in CX3CR1+ tissue-resident skeletal muscle macrophages prevents muscle recovery after influenza A virus-induced pneumonia in aged mice

Project description:Skeletal muscle dysfunction in survivors of pneumonia is a major cause of lasting morbidity that disproportionately affects older individuals. We found that skeletal muscle recovery was impaired in aged compared with young mice after influenza A virus-induced pneumonia. In young mice, recovery of muscle loss was associated with expansion of tissue-resident skeletal muscle macrophages and downregulation of MHC II expression, followed by a proliferation of muscle satellite cells. These findings were absent in aged mice and in mice deficient in Cx3cr1. Transcriptomic profiling of tissue-resident skeletal muscle macrophages from aged compared with young mice showed downregulation of pathways associated with phagocytosis and proteostasis, and persistent upregulation of inflammatory pathways. Consistently, skeletal muscle macrophages from aged mice failed to downregulate MHCII expression during recovery from influenza A virus induced pneumonia and showed impaired phagocytic function in vitro. Like aged animals, mice deficient in the phagocytic receptor Mertk showed no macrophage expansion, MHCII downregulation or satellite cell proliferation and failed to recover skeletal muscle function after influenza A pneumonia. Our data suggest that a loss of phagocytic function in a CX3CR1+ tissue-resident skeletal muscle macrophage population in aged mice precludes satellite cell proliferation and recovery of skeletal muscle function after influenza A pneumonia.

2020-08-05 | GSE142580 | GEO

Geriatric muscle stem cells switch reversible quiescence into senescence (Set 3; Adult vs. Young)

Project description:Regeneration of skeletal muscle depends on a population of adult stem cells (satellite cells) that remain quiescent throughout life. Satellite cell regenerative functions decline with aging. We report that geriatric satellite cells, compared to old and adult cells, are incapable of maintaining their normal quiescent state in muscle homeostatic conditions, and this irreversibly affects their intrinsic regenerative and self-renewal capacities. We analyzed the global changes in gene expression occurring within muscle stem cells (satellite cells) in homeostatic conditions during physiological aging. Pure satellite cell populations from dissociated skeletal muscle from Young (2-3 months) and Adult (6 months) mice were isolated using a well-established flow cytometry protocol gating on integrin a7(+)/CD34(+) (positive selection) and Lin- (CD31, CD45, CD11b, Sca1) (negative selection).

2013-12-31 | E-GEOD-53726 | biostudies-arrayexpress

Geriatric muscle stem cells switch reversible quiescence into senescence (Set 1; Geriatric vs. Young)

Project description:Regeneration of skeletal muscle depends on a population of adult stem cells (satellite cells) that remain quiescent throughout life. Satellite cell regenerative functions decline with aging. Here we report that geriatric satellite cells, compared to old cells, are incapable of maintaining their normal quiescent state in muscle homeostatic conditions, and this irreversibly affects their intrinsic regenerative and self-renewal capacities. We analyzed the global changes in gene expression occurring within muscle stem cells (satellite cells) in homeostatic conditions during physiological aging. Pure satellite cell populations from dissociated skeletal muscle from Young (2-3 months) and Geriatric (28-32 months) mice were isolated using a well-established flow cytometry protocol gating on integrin a7(+)/CD34(+) (positive selection) and Lin- (CD31, CD45, CD11b, Sca1) (negative selection).

2013-12-31 | E-GEOD-53724 | biostudies-arrayexpress

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