Healthy aging of skeletal muscle: Insights from a combined morphological and multiomic study
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE257558 | GEO | 2024/10/09
REPOSITORIES: GEO
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Project description:Age-related skeletal muscle atrophy or sarcopenia is a significant societal problem that is becoming amplified as the world’s population continues to increase. A critical contributor to sarcopenia is the loss in the number and function of muscle stem cells, which maintain tissue homeostasis and regenerate damage. The molecular mechanisms that govern muscle stem cell aging encompass changes across multiple regulatory layers and are integrated by the three-dimensional organization of the genome. To quantitatively understand how hierarchical chromatin architecture changes during muscle stem cell aging, we generated 3D chromatin conformation maps (Hi-C) and integrated these datasets with multi-omic (chromatin accessibility and transcriptome) profiles from bulk populations and single cells. We observed that muscle stem cells display static behavior at global scales of chromatin organization during aging and extensive rewiring of local contacts at finer scales that were associated with variations in transcription factor binding and aberrant gene expression. These data provide insights into genome topology as a regulator of molecular function in stem cell aging.
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Project description:Age-related skeletal muscle atrophy or sarcopenia is a significant societal problem that is becoming amplified as the world’s population continues to increase. A critical contributor to sarcopenia is the loss in the number and function of muscle stem cells, which maintain tissue homeostasis and regenerate damage. The molecular mechanisms that govern muscle stem cell aging encompass changes across multiple regulatory layers and are integrated by the three-dimensional organization of the genome. To quantitatively understand how hierarchical chromatin architecture changes during muscle stem cell aging, we generated 3D chromatin conformation maps (Hi-C) and integrated these datasets with multi-omic (chromatin accessibility and transcriptome) profiles from bulk populations and single cells. We observed that muscle stem cells display static behavior at global scales of chromatin organization during aging and extensive rewiring of local contacts at finer scales that were associated with variations in transcription factor binding and aberrant gene expression. These data provide insights into genome topology as a regulator of molecular function in stem cell aging.
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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.
2013-09-01 | GSE47104 | GEO
Project description:Aging is accompanied by a loss of muscle mass and function, termed sarcopenia, causing numerous morbidities and economic burdens in human populations. Mechanisms implicated in age-related sarcopenia include inflammation, muscle stem cell depletion, mitochondrial dysfunction and loss of motor neurons, but whether there are key drivers of sarcopenia is not yet known. To gain deeper insights into age-related sarcopenia, we performed transcriptome profiling on lower limb muscle biopsies from 72 young, old and sarcopenic subjects using bulk RNA-seq (N = 72) and single-nuclei RNA-seq (N = 17). Using this combined approach, we discovered novel changes in gene expression that occur with age and sarcopenia in multiple cell types comprising mature skeletal muscle. Notably, we found increased expression of the genes MYH8 and PDK4, and decreased expression of the gene IGFN1, in old muscle. We also identified a small population of nuclei that express CDKN1A, present only in aged samples, consistent with P21CIP1 senescence in this subpopulation. Our findings identify unique cellular sub-populations populations in aged and sarcopenic skeletal muscle, which will facilitate the development of new therapeutic strategies to combat age-related sarcopenia.
2022-03-31 | GSE167186 | GEO
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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