Mus musculus strain:C57BL/6J
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ABSTRACT:
PROVIDER: PRJDB16391 | ENA |
REPOSITORIES: ENA
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Project description:Utilizing glycerol intramuscular injections in M. musculus provides a model of skeletal muscle damage followed by skeletal muscle regeneration. In particular, glycerol-induced muscle injury triggers accute activation of muscle Fibro/Adipogenic Progenitors, also called FAPs. However, aging dramatically impairs FAP function. We characterized genome-wide expression profiles of young and old FAPs in the non-proliferative and activated state, freshly isolated to non-injured or damaged muscles, respectively. Our goal was to uncover new regulatory signalings specific to FAP entry into the activation program that are affected with age.
2018-11-26 | GSE92508 | GEO
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: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:Fibro adipogenic progenitors (FAPs) promote satellite cell differentiation in adult skeletal muscle regeneration. However, in pathological conditions, FAPs are responsible for fibrosis and fatty infiltrations. Here we show that the NOTCH pathway negatively modulates FAP differentiation both in vitro and in vivo. However, FAPs isolated from young dystrophin- deficient mdx mice are insensitive to this control mechanism. An unbiased mass spectrometry-based proteomic analysis of FAPs from muscles of wild type and mdx mice, suggest that the synergistic cooperation between NOTCH and inflammatory signals controls FAP differentiation. Remarkably, we demonstrated that factors released by hematopoietic cells restore the sensitivity to NOTCH adipogenic inhibition in mdx FAPs. These results offer a basis for rationalizing pathological ectopic fat infiltrations in skeletal muscle and may suggest new therapeutic strategies to mitigate the detrimental effects of fat depositions in muscles of dystrophic patients.
2019-06-24 | PXD014195 | Pride
Project description:Skeletal muscle unloading due to joint immobilization induces skeletal muscle atrophy. However, the skeletal muscle proteome response to limb immobilization has not been investigated using SWATH methods. This study quantitatively characterized the muscle proteome at baseline, and after 3 and 14 d of unilateral lower limb (knee-brace) immobilization in 18 healthy young men (25.4 ±5.5 y, 81.2 ±11.6 kg). All muscle biopsies were obtained from the vastus lateralis muscle. Unilateral lower limb immobilization was preceded by four-weeks of exercise training to standardise acute training history, and 7 days of dietary provision to standardise energy/macronutrient intake. Dietary intake was also standardised/provided throughout the 14 d immobilization period.
2022-08-25 | PXD034908 | Pride
Project description:Skeletal muscle experiences a decline in lean mass and regenerative potential with age, in part due to intrinsic changes in progenitor cells. However, it remains unclear if age-related changes in progenitors persist across a differentiation trajectory or if new age-related changes manifest in differentiated cells. To investigate this possibility, we performed single cell RNA-seq on muscle mononuclear cells from young and aged mice and profiled muscle stem cells (MuSCs) and fibro/adipose progenitors (FAPs) after differentiation. Differentiation increased the magnitude of age-related change in MuSCs and FAPs, but also masked a subset of age-related changes present in progenitors. Using a dynamical systems approach and RNA velocity, we found that aged MuSCs follow the same differentiation trajectory as young cells, but stall in differentiation near a commitment decision. Our results suggest that age-related changes are plastic across differentiation trajectories and that fate commitment decisions are delayed in aged myogenic cells.
2021-04-16 | GSE145256 | GEO
Project description:Our laboratory previously demonstrated that perivascular stem/stromal cells (CD146+ pericytes) can effectively recover muscle mass after a period of immobilization in young adult mice. However, cell-based therapies are problematic in aged mouse models due to lack of viability upon transplantation. Therefore, the purpose of this study was to develop a pericyte-based, cell-free strategy to recover muscle mass after disuse in aged mice. Single-cell RNA sequencing (scRNA-Seq) was performed on adult mouse skeletal muscle after two weeks of unilateral hindlimb immobilization, which revealed that muscle-resident pericytes uniquely upregulate the long noncoding RNA Malat1, a negative regulator of Nrf2, and fail to induce antioxidant gene expression in response to reactive oxygen species (ROS; H2O2). This information was used to guide the design of a strategy in which healthy donor pericytes were stimulated with ROS to produce small extracellular vesicles (EVs) that were subsequently transplanted into 4- and 24-26-month-old C57BL/6 mice after two weeks of unilateral hindlimb immobilization. H2O2-primed healthy muscle-derived pericytes produced EVs in culture that effectively reduced restored myofiber CSA in both adult (p=0.009) and aged (p=0.006) muscle after disuse. In contrast, unprimed pericyte-derived EVs did not influence myofiber size. Neither primed, nor unprimed EVs recovered capillary density, yet both stimulated collagen turnover. Healthy ROS-primed pericyte-derived small EVs effectively improve skeletal muscle recovery after immobilization, representing a novel cell-free approach to rebuild muscle mass in older adults after a period of disuse.
2022-09-28 | GSE185560 | GEO
Project description:A mechanistic understanding of the age-related impairment to skeletal muscle regrowth following disuse atrophy as well as therapies to augment recovery in the aged are currently lacking. Mechanotherapy in the form of cyclic compressive loading has been shown to benefit skeletal muscle under a variety of paradigms, but not during the recovery from disuse in aged muscle. To determine whether mechanotherapy promotes extracellular matrix (ECM) remodeling, a critical aspect of muscle recovery after atrophy, we performed single cell RNA sequencing (scRNA-seq) of gastrocnemius muscle cell populations, stable isotope tracing of intramuscular collagen, and histology of the ECM in adult and aged rats recovering from disuse, with and without mechanotherapy. ECM remodeling-related gene expression in fibro-adipose progenitor cells (FAPs) was absent in aged compared to adult muscle following 7 days of recovery, and instead were enriched in chemoattractant genes. There was a significantly lower expression of genes related to phagocytic activity in aged macrophages during recovery, despite enriched chemokine gene expression of numerous stromal cell populations, including FAPs and endothelial cells. Mechanotherapy reprogrammed the transcriptomes of both FAPs and macrophages in aged muscle recovering from disuse to restore ECM-and phagocytosis-related gene expression, respectively. Stable isotope labeling of intramuscular collagen and histological evaluation confirmed mechanotherapy-mediated remodeling of the ECM in aged muscle recovering from disuse. In summary, our results highlight mechanisms underlying age-related impairments during the recovery from disuse atrophy and promote mechanotherapy as an intervention that reprograms the muscle transcriptional environment more similar to that of adult skeletal muscle.
2022-03-31 | GSE184413 | GEO
Project description:In our study, we used hindlimb unloading rat model to study fibro-adipogenic progenitor cells (FAPs) condition in muscle atrophy. We have purified FAPs from m. soleus from control rats and after 7 and 14 days of immobilization (HS7, HS14). Also, we performed adipogenic differentiation of FAPS in vitro during 3 days.
2023-04-10 | GSE228869 | GEO
Project description:Comprehensive analyses of mRNA expression were performed using three different cell populations isolated from skeletal muscle of young and aged mice to investigate age-related changes of each cell population.
2020-02-14 | GSE126665 | GEO