Development of a Pericyte-Based Cell-Free Strategy to Recover Aged Skeletal Muscle After Disuse
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ABSTRACT:
PROVIDER: PRJNA769671 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16249202_1.fastq.gz | Fastqsanger.gz | |||
| SRR16249202_2.fastq.gz | Fastqsanger.gz | |||
| SRR16249203_1.fastq.gz | Fastqsanger.gz | |||
| SRR16249203_2.fastq.gz | Fastqsanger.gz | |||
| SRR16249204_1.fastq.gz | Fastqsanger.gz |
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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:Extended periods of bed rest and limb immobilization are required for healing post-injury or disease, yet disuse can result in significant muscle atrophy and decreased quality of life in older adults. Physical rehabilitation is commonly prescribed to recover these deficits, yet accumulation of reactive oxygen species and sustained rates of protein degradation persist during the rehabilitation period that can significantly delay or prevent recovery. Pericytes, considered the primary mesenchymal and vascular stromal cell in skeletal muscle, secrete beneficial factors that maintain baseline muscle mass, yet minimal information exists regarding the pericyte response to disuse and recovery. In the current study, single-cell RNA sequencing and functional assays were performed to demonstrate that pericytes in mouse skeletal muscle lose the capacity to synthesize antioxidants during disuse and recovery. This information was used to guide the design of a strategy in which healthy donor pericytes were stimulated with hydrogen peroxide (H2 O2 ) to produce small extracellular vesicles (sEVs) that effectively restored myofibre size in adult and aged muscle after disuse. Proteomic assessment detected 11 differentially regulated proteins in primed sEVs that may account for recovery of muscle, including proteins associated with extracellular matrix composition and anti-inflammatory and antioxidant processes. This study demonstrates that healthy H2 O2 -primed pericyte-derived sEVs effectively improve skeletal muscle recovery after immobilization, presenting a novel acellular approach to rebuild muscle mass in older adults after a period of disuse. KEY POINTS: Previous studies suggest that prolonged oxidative stress is a barrier to skeletal muscle recovery after a period of immobilization. In this study we demonstrate that muscle-resident perivascular stromal cells (pericytes) become dysfunctional and lack the capacity to mount an antioxidant defence after disuse in mice. Hydrogen peroxide treatment of healthy pericytes in vitro simulates the release of small extracellular vesicles (sEVs) that effectively recover skeletal muscle fibre size and extracellular matrix remodelling in young adult and aged mice after disuse. Pericyte-derived sEVs present a novel acellular strategy to recover skeletal muscle after disuse.
| S-EPMC9492804 | biostudies-literature
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:To identify atrophy genes directly targeted by Bcl-3 transactivator at a genome wide level, we performed whole transcript expression array and ChIP-seq for muscles from weight bearing or 5-day hind limb unloaded mice. Genes that showed increased expression with unloading and a Bcl-3 peak in the promoter (from ChIP-seq data) were considered as Bcl-3 direct targets during disuse atrophy. Using ChIP array, we identified 241 direct targets for Bcl-3. Our data describe Bcl-3 as a global regulator both of the proteolysis and the change in energy metabolism that are essential components of muscle atrophy due to disuse. Disuse skeletal muscle atrophy was induced by hind limb unloading. Weight bearing (WB) or 5-day hind limb unloaded (HU) muscles were harvested for total RNA isolation and processed for whole transcript expression profiling. We chose to examine gene expression and Bcl-3 binding from 5-day unloaded muscles because our previous time course study of disuse atrophy suggested that most genes are differentially regulated at this time point, and thus, would best represent the time for Bcl-3 binding to the gene targets of the NF-kB transcriptional network.
2012-11-10 | E-GEOD-40578 | biostudies-arrayexpress
Project description:Aged skeletal muscle is characterized by impaired muscle recovery following disuse and coincides with an impaired muscle pro-inflammatory macrophage response. Macrophage inflammatory status (polarization) is regulated by its metabolic state, but to date, little is understood of macrophage metabolism and its relation to macrophage polarization in the context of muscle recovery and aging. Therefore, the purpose of this study was to thoroughly characterize macrophage metabolism and polarization in aged muscle during early recovery from disuse atrophy using single cell RNA sequencing and functional assays. Young (4-5 mo) and old (20-22 mo) male C57BL/6 mice underwent 14 days of hindlimb unloading followed by 4 days of ambulatory recovery. CD45+ cells were isolated from solei muscles and analyzed using 10x Genomics single cell RNA sequencing. We found that aged M1 macrophage clusters were characterized with an impaired inflammatory and glycolytic transcriptome and this impairment was accompanied by a suppression of HIF-1α and its immediate downstream target GLUT1.
2021-08-12 | GSE158987 | GEO
Project description:Pericytes are intrinsic components of vessels that regulate vascular stability and permeability. Aberrant vascularization is a hallmark of cancer, although the contribution of pericytes to this process is poorly understood. Here, we undertook a combined computational and experimental strategy to identify the molecular reprogramming of prostate pericytes during cancer pathogenesis and progression. Analysis of human prostate cancer and murine mouse models showed that prostate tumors exhibit a disequilibrium between endothelial and pericyte content with prognostic potential. Deeper molecular analysis revealed that there is no overt loss of pericytes in prostate tumors, but rather a disfunction that is concomitant with altered expression of a subset of cellular markers. We translate this finding into a simplified signature that discriminates pericyte abundance versus function. Leveraging single-cell RNA sequencing data, we find that TGFβ governs the molecular changes that underlie pericyte disfunction in tumors. This mechanism is associated with reduced pericyte contractility, enlargement of vascular lumen and increased permeability in prostate cancer. Altogether, this study revisits the paradigm of reduced number of pericyte in favor of their disfunction in tumors, and the importance of paracrine signaling in this process.
2025-10-03 | GSE278801 | GEO
Project description:Loss of muscle mass and strength following disuse followed by impaired muscle recovery likely contribute to sarcopenia in older adults. Metformin and leucine individually have shown positive effects in skeletal muscle during atrophy conditions but have not been evaluated in combination nor under the conditions of disuse atrophy and recovery in aging. The purpose of this study was to determine if a dual treatment of metformin and leucine (MET+LEU) would prevent disuse-induced atrophy and/or promote muscle recovery in aged mice (22-24 mo). We were also interested if these muscle responses correspond to changes in satellite cells and ECM abundance. Aged mice were subjected to 14 days of hindlimb unloading (HU) followed by 7 or 14 days of reloading (7 or 14d RL). Metformin (MET), leucine (LEU), or MET+LEU was administered via drinking water and were compared to Vehicle-treated mice. We observed that MET+LEU increased whole body grip strength, muscle specific force and satellite cell abundance during HU but did not alter muscle size during HU or RL. Moreover, MET+LEU treatment increased ECM turnover driven by a decrease in collagen IV content during 7 and 14d RL. Transcriptome analysis revealed that MET+LEU altered Gene Set Enrichment Analysis hallmark pathways related to inflammation and myogenesis during HU. Together , MET+LEU was able to improve muscle quality during disuse and recovery in aging possibly by increasing muscle satellite cell content and reducing excessive ECM accumulation.
2021-09-01 | GSE167462 | GEO
Project description:Proteomics analysis can reveal the differences of protein expression between mural cells (known as pericytes) from normal adjacent tissues (NPC) and tumors (TPC), implying the effectiveness of pericyte to tumor.
2021-08-24 | PXD026963 | Pride
Project description:Disuse atrophy is a common clinical phenomenon which significantly impacts muscle function and activities of daily living. In this study, we did expression profiling to identify transcriptional pathways associated with muscle remodeling in a clinical model of disuse. Keywords: Differentiation design
2007-08-28 | GSE8872 | GEO
Project description:Disuse atrophy is a common clinical phenomenon which significantly impacts muscle function and activities of daily living. In this study, we did expression profiling to identify transcriptional pathways associated with muscle remodeling in a clinical model of disuse. Keywords: Differentiation design 28 Skeletal muscle biopsies from the medial gastrocnemius in patients with an ankle fracture (4 patients, 8 profiles) and from healthy volunteers (2 subjects, 4 profiles) subjected to 4-11 days of mobilization, as well as from the non-immobilized contralateral legs (16 profiles).
2007-08-28 | E-GEOD-8872 | biostudies-arrayexpress