The immune landscape of murine skeletal muscle regeneration and aging
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE279741 | GEO | 2024/10/18
REPOSITORIES: GEO
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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
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.
2014-05-08 | GSE50821 | GEO
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
Project description:In aging, skeletal muscle strength and regenerative capacity declines due, in part, to functional impairment of muscle stem cells MuSCs, yet the underlying mechanisms remain elusive. Here we capitalize on mass-cytometry to identify high CD47 expression as a hallmark of dysfunctional MuSCs CD47hi with impaired regenerative capacity that predominate with aging. The prevalent CD47 hi MuSC subset suppresses the residual functional CD47 lo MuSC subset through a paracrine signaling loop, leading to impaired proliferation. We uncover that elevated CD47 levels on aged MuSCs result from increased U1 snRNA expression, which disrupts alternative polyadenylation. The deficit in aged MuSC function in regeneration can be overcome either by morpholino-mediated blocking of CD47 alternative polyadenylation or antibody blockade of CD47 signaling, leading to improved regeneration in aged mice, with therapeutic implications. Our findings highlight a previously unrecognized age-dependent alteration in CD47 levels and function in MuSCs, which underlies reduced muscle repair in aging.
2022-11-16 | GSE198249 | GEO
Project description:Skeletal muscle function and regenerative capacity decline during aging, yet factors driving these changes are incompletely understood. Muscle regeneration requires temporally coordinated transcriptional programs to drive myogenic stem cells to activate, proliferate, fuse to form myofibers, and to mature myonuclei, restoring muscle function after injury. We assessed global changes in myogenic transcription programs distinguishing muscle regeneration in aged mice from young mice by comparing pseudotime trajectories from single-nucleus RNA sequencing of myogenic nuclei. Aging-specific differences in coordinating myogenic transcription programs necessary for restoring muscle function occur following muscle injury, likely contributing to compromised regeneration in aged mice. Differences in pseudotime alignment of myogenic nuclei when comparing aged to young mice via Dynamic Time-Warping revealed pseudotemporal differences becoming progressively more severe as regeneration proceeds. Disruptions in timing of myogenic gene expression programs may contribute to incomplete skeletal muscle regeneration and declines in muscle function as organisms age.
2023-06-12 | GSE180225 | GEO
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
Project description:During aging, the number and functionality of muscle stem cells (MuSCs) decreases leading to impaired regeneration of aged skeletal muscle. In addition to intrinsic changes in aged MuSCs, extracellular matrix (ECM) proteins deriving from other cell types, e.g., fibrogenic-adipogenic progenitor cells (FAPs), contribute to the aging phenotype of MuSCs and impaired regeneration in the elderly. So far, no comprehensive analysis on how age-dependent changes in the whole skeletal muscle proteome affect MuSC function have been conducted. Here, we investigated age-dependent changes in the proteome of different skeletal muscle types by applying deep quantitative mass spectrometry. We identified 183 extracellular matrix proteins that show different abundances in skeletal muscles of old mice. By integrating single cell sequencing data, we reveal that transcripts of those ECM proteins are mainly expressed in FAPs, suggesting that FAPs are the main contributors to ECM remodelling during aging. We functionally investigated one of those ECM molecules, namely Smoc2, which is aberrantly expressed during aging. We show that Smoc2 levels are elevated during regeneration and that its accumulation in the aged MuSC niche causes impairment of MuSCs function through constant activation of integrin/MAPK signaling. In vivo, supplementation of exogenous Smoc2 hampers the regeneration of young muscles following serial injuries, leading to a phenotype reminiscent of regenerating aged skeletal muscle. Taken together, we provide a comprehensive resource of changes in the composition of the ECM of aged skeletal muscles, we pinpoint the cell types driving these changes, and we identify a new niche protein causing functional impairment of MuSCs thereby hampering the regeneration capacity of skeletal muscles.
2021-11-25 | PXD015728 | Pride
Project description:During aging, the number and functionality of muscle stem cells (MuSCs) decreases leading to impaired regeneration of aged skeletal muscle. In addition to intrinsic changes in aged MuSCs, extracellular matrix (ECM) proteins deriving from other cell types, e.g., fibrogenic-adipogenic progenitor cells (FAPs), contribute to the aging phenotype of MuSCs and impaired regeneration in the elderly. So far, no comprehensive analysis on how age-dependent changes in the whole skeletal muscle proteome affect MuSC function have been conducted. Here, we investigated age-dependent changes in the proteome of different skeletal muscle types by applying deep quantitative mass spectrometry. We identified 183 extracellular matrix proteins that show different abundances in skeletal muscles of old mice. By integrating single cell sequencing data, we reveal that transcripts of those ECM proteins are mainly expressed in FAPs, suggesting that FAPs are the main contributors to ECM remodelling during aging. We functionally investigated one of those ECM molecules, namely Smoc2, which is aberrantly expressed during aging. We show that Smoc2 levels are elevated during regeneration and that its accumulation in the aged MuSC niche causes impairment of MuSCs function through constant activation of integrin/MAPK signaling. In vivo, supplementation of exogenous Smoc2 hampers the regeneration of young muscles following serial injuries, leading to a phenotype reminiscent of regenerating aged skeletal muscle. Taken together, we provide a comprehensive resource of changes in the composition of the ECM of aged skeletal muscles, we pinpoint the cell types driving these changes, and we identify a new niche protein causing functional impairment of MuSCs thereby hampering the regeneration capacity of skeletal muscles.
2021-11-25 | PXD015616 | Pride
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.
2014-05-26 | GSE47401 | GEO
Project description:Background: Sarcopenia is a common and progressive skeletal muscle disorder characterized by atrophic muscle fibers and contractile dysfunction. Accumulating evidence shows that the number and function of satellite cells (SCs) decline and become impaired during aging, which may contribute to impaired regenerative capacity. A series of myokines/ small extracellular vesicles (sEVs) released from muscle fibers regulate metabolism in muscle and extramuscular tissues in an autocrine/paracrine/endocrine manner during muscle atrophy. It is still unclear whether myokines/sEVs derived from muscle fibers can affect satellite cell function during aging. Methods: Aged mice were used to investigate changes in the myogenic capacity of SCs during aging-induced muscle atrophy. The effects of atrophic myotube-derived sEVs on satellite cell differentiation were investigated by biochemical methods and immunofluorescence staining. Small RNA sequencing was performed to identify differentially expressed sEV microRNAs (miRNAs) between the control myotubes and atrophic myotubes. The target genes of the miRNA were predicted by bioinformatics analysis and verified by luciferase activity assays. The effects of identified miRNA on the myogenic capacity of SCs in vivo were investigated by intramuscular injection of adeno-associated virus (AAV) to overexpress or silence miRNA in skeletal muscle. Results: Our study showed that the myogenic capacity of SCs was significantly decreased (50%, n = 6, P < 0.001) in the tibialis anterior muscle of aged mice. We showed that atrophic myotube-derived sEVs inhibited satellite cell differentiation in vitro (n = 3, P < 0.001) and in vivo (35%, n = 6, P < 0.05). We also found that miR-690 was the most highly enriched miRNA among all the screened sEV miRNAs in atrophic myotubes [Log2 (Fold Change) = 7, P<0.001], which was verified in the atrophic muscle of aged mice (3-fold, n = 6, P < 0.001) and aged humans (2.8-fold, n = 10, P < 0.001). miR-690 can inhibit myogenic capacity of SCs by targeting myocyte enhancer factor 2, including Mef2a, Mef2c, and Mef2d, in vitro (n=3, P < 0.05) and in vivo (n=6, P < 0.05). Specific silencing of miR-690 in the muscle can promote satellite cell differentiation (n = 6, P < 0.001) and alleviate muscle atrophy in aged mice (n = 6, P < 0.001). Conclusions: Our study demonstrated that atrophic muscle fiber-derived sEV miR-690 may inhibit satellite cell differentiation by targeting myocyte enhancer factor 2 during aging.
2022-12-21 | GSE211885 | GEO