Distinct and additive effects of calorie restriction and rapamycin in aging skeletal muscle [CR data set]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE171322 | GEO | 2022/03/02
REPOSITORIES: GEO
Similar Datasets
Project description:Calorie restriction (CR) is a dietary intervention that extends lifespan and healthspan in a variety of organisms. CR improves mitochondrial energy production, fuel oxidation and reactive oxygen species scavenging in skeletal muscle and other tissues, and these processes are thought to be critical to the benefits of CR. PGC-1a is a transcriptional coactivator that regulates mitochondrial function and is induced by CR. Consequently, many of the mitochondrial and metabolic benefits of CR are attributed to increased PGC-1a activity. To test this model for the first time, we examined the metabolic and mitochondrial response to CR in mice lacking skeletal muscle PGC-1a (MKO). Surprisingly, MKO mice demonstrated a normal improvement in glucose homeostasis in response to CR, indicating that skeletal muscle PGC-1a is dispensable for the whole-body benefits of CR. In contrast, gene expression profiling and electron microscopy demonstrated that PGC-1a is required for the full CR-induced increases in mitochondrial gene expression and mitochondrial density in skeletal muscle. These results demonstrate that PGC-1a is a major regulator of the mitochondrial response to CR in skeletal muscle, but surprisingly show that neither PGC-1a nor mitochondrial biogenesis in skeletal muscle are required for the metabolic benefits of CR. Control (FLOX) and PGC-1a skeletal muscle specific knock out (MKO) mice were placed on a control diet [C] or a calorie restriction diet [CR] for 12 weeks. RNA was isolated from TA/EDL muscles for microarray analysis. The following numbers of mice were analyzed from each group: C FLOX: n = 6; C MKO: n = 7; CR FLOX: n = 6; CR MKO: n = 7. Mice were mixed C57/BL6 and 129 background.
2012-02-04 | E-GEOD-34773 | biostudies-arrayexpress
Project description:Calorie restriction (CR) is a dietary intervention that extends lifespan and healthspan in a variety of organisms. CR improves mitochondrial energy production, fuel oxidation and reactive oxygen species scavenging in skeletal muscle and other tissues, and these processes are thought to be critical to the benefits of CR. PGC-1a is a transcriptional coactivator that regulates mitochondrial function and is induced by CR. Consequently, many of the mitochondrial and metabolic benefits of CR are attributed to increased PGC-1a activity. To test this model for the first time, we examined the metabolic and mitochondrial response to CR in mice lacking skeletal muscle PGC-1a (MKO). Surprisingly, MKO mice demonstrated a normal improvement in glucose homeostasis in response to CR, indicating that skeletal muscle PGC-1a is dispensable for the whole-body benefits of CR. In contrast, gene expression profiling and electron microscopy demonstrated that PGC-1a is required for the full CR-induced increases in mitochondrial gene expression and mitochondrial density in skeletal muscle. These results demonstrate that PGC-1a is a major regulator of the mitochondrial response to CR in skeletal muscle, but surprisingly show that neither PGC-1a nor mitochondrial biogenesis in skeletal muscle are required for the metabolic benefits of CR.
2012-02-04 | GSE34773 | GEO
Project description:Purpose: Despite demonstrating that the overall effect of long-term rapamycin-treatment is overwhelmingly positive in aging skeletal muscle, we observed muscle-specificity in the responsiveness to rapamycin, leading us to hypothesize that the primary drivers of age-related muscle loss and therefore effective intervention strategies may differ between muscles. To address this question and dissect the key signaling nodes associated with mTORC1-driven muscle aging, we created a comprehensive multi-muscle gene expression atlas in adult, sarcopenic and rapamycin-treated mice using RNA-seq. Methods: To examine the impact of long-term rapamycin treatment, male C57BL/6 mice were fed encapsulated rapamycin incorporated into a standardized AIN93M diet at 42 ppm (i.e. mg per kg of food), corresponding to a dose of ~4 mg·kg-1·day-1, from 15- to 30-months of age. This dose of rapamycin has been shown to extend lifespan maximally in male C57BL/6 mice. We performed RNA-seq on gastrocnemius (GAS), tibialis anterior (TA), triceps brachii (TRI) and soleus (SOL) muscles from each of six mice for 10m, 30m and 30mRM groups. The four muscle types were chosen to encompass fore- and hindlimb locations (e.g. TRI and GAS); slow and fast contraction properties (e.g. SOL and GAS); anterior and posterior positioning (e.g. TA and GAS) and the extent of protection by rapamycin (TA and TRI: protected; SOL: partiallly protected; GAS: not protected). Results: Age-related gene expression changes were remarkably consistent across the four different muscles, varying only in magnitude. Despite having the smallest age-related muscle loss of the four muscles, TA had the strongest age-related gene expression response which was associated with an increased reinnervation response. Despite the strong between-muscle commonality of age-related changes, gene expression responses to prolonged rapamycin treatment differed substantially between muscles. Rapamycin partially reversed many age-related changes in mRNA expression in the TA and TRI, but not in SOL or GAS muscle. Principle component analysis (PCA) showed that rapamycin had common 'anti-aging' effects on all muscles, while also exerting muscle-specific pro-aging effects on muscles not protected by rapamycin. Conclusions: Sustained, muscle fiber-specific mTORC1 activity drives sarcopenia-like gene expression programs, and the hyperactive mTORC1 seen in sarcopenic muscle may therefore contribute to sarcopenia.
2020-06-19 | GSE139204 | GEO
Project description:Here, we show that CR enhances regenerative capacity of the intestinal epithelium as a result of increased number of reserve ISCs. We observe that precise regulation of mechanistic target of Rapamycin complex 1 (mTORC1) signaling plays a significant role in regulation of sensitivity of reserve intestinal stem cells to injury and that premature activation of mTORC1 signaling through nutrient modulation, at the time of damage, leads to poor regeneration outcome. These data delineate a critical role for mTORC1 signaling in epithelial regeneration and inform clinical strategies based on nutrient modulation of mTORC1 activity.
2018-01-15 | GSE109002 | GEO
Project description:Although caloric restriction (CR) was first shown to extend the lifespan of rodents over 75 years ago, the underlying mechanisms remain unclear. Additionally, the majority of published studies have focused on the effects of short-term CR. To better understand cell signaling alterations in a tissue known to be highly impacted by CR, we sought to assess the impact of aging and lifelong CR on skeletal muscle protein phosphorylation dynamics. We performed phosphoproteomic analysis on skeletal muscle from young mice, old mice fed on an ad libitum diet, and old mice fed a CR diet. This analysis revealed distinct phosphoproteomic signatures associated with both aging and diet. Importantly, CR appeared to promote a signature that was more similar to young mice than old mice fed on an ad lib diet. From the phosphorylation measurements on its known substrates, we deciphered that aging promotes Protein kinase A (PKA) signaling, and CR inhibits this signaling cascade. Given the demonstrated role of PKA signaling as a “pro-aging” pathway in various model organisms, including yeast and mice, we propose that CR exerts its longevity-enhancing effects partially via the suppression of this pathway.
2021-01-30 | PXD018455 | JPOST Repository
Project description:The mechanistic target of rapamycin complex 1 (mTORC1) controls cellular anabolism in response to nutrient sufficiency and growth factor signaling, and genetic and pharmacological inhibition of mTORC1 extends longevity across eukaryotes. Up to date, mouse models to analyze the mechanisms of aging governed by mTORC1 has been limited by detrimental pleiotropic consequences of genetically-increased mTORC1 activity in mice. RragcS74N/+, RragcS74C/+ and RragcT89N/+ knock-in mice endogenously express active mutant variants of RagC, a GTPase that signaling nutrient sufficiency to mTORC1. Rragcmutant/+ mice show an only moderate increase in nutrient signaling to mTORC1, and after one year of life exhibit multiple features of a premature aging phenotype that include prominent senescence in peripheral organs, parenchymal expression of inflammatory and chemo-attractant molecules, increased myeloid inflammation and extensive features of inflammaging. In vivo transplantation and ex vivo functional experiments with bone marrow-derived cells show that myeloid cells are abnormally activated by parenchymal signals evoked from Rragcmut/+ organs, to where myeloid cells extravasate to inflict additional inflammatory damage. Therapeutic suppression of myeloid inflammation in old Rragcmut/+ attenuates features of premature aging and extends longevity. We provide the first genetic link of elevated nutrient – mTORC1 activity and premature aging in mammals, and provide support for a two-component model in which increased nutrient signaling drives parenchymal damage and myeloid inflammation precipitates organ deterioration and accelerated aging.
2024-04-02 | GSE221286 | GEO
Project description:The mechanistic target of rapamycin complex 1 (mTORC1) controls cellular anabolism in response to nutrient sufficiency and growth factor signaling, and genetic and pharmacological inhibition of mTORC1 extends longevity across eukaryotes. Up to date, mouse models to analyze the mechanisms of aging governed by mTORC1 has been limited by detrimental pleiotropic consequences of genetically-increased mTORC1 activity in mice. RragcS74N/+, RragcS74C/+ and RragcT89N/+ knock-in mice endogenously express active mutant variants of RagC, a GTPase that signaling nutrient sufficiency to mTORC1. Rragcmutant/+ mice show an only moderate increase in nutrient signaling to mTORC1, and after one year of life exhibit multiple features of a premature aging phenotype that include prominent senescence in peripheral organs, parenchymal expression of inflammatory and chemo-attractant molecules, increased myeloid inflammation and extensive features of inflammaging. In vivo transplantation and ex vivo functional experiments with bone marrow-derived cells show that myeloid cells are abnormally activated by parenchymal signals evoked from Rragcmut/+ organs, to where myeloid cells extravasate to inflict additional inflammatory damage. Therapeutic suppression of myeloid inflammation in old Rragcmut/+ attenuates features of premature aging and extends longevity. We provide the first genetic link of elevated nutrient – mTORC1 activity and premature aging in mammals, and provide support for a two-component model in which increased nutrient signaling drives parenchymal damage and myeloid inflammation precipitates organ deterioration and accelerated aging.
2024-04-02 | GSE221285 | GEO
Project description:The mechanistic target of rapamycin complex 1 (mTORC1) controls cellular anabolism in response to nutrient sufficiency and growth factor signaling, and genetic and pharmacological inhibition of mTORC1 extends longevity across eukaryotes. Up to date, mouse models to analyze the mechanisms of aging governed by mTORC1 has been limited by detrimental pleiotropic consequences of genetically-increased mTORC1 activity in mice. RragcS74N/+, RragcS74C/+ and RragcT89N/+ knock-in mice endogenously express active mutant variants of RagC, a GTPase that signaling nutrient sufficiency to mTORC1. Rragcmutant/+ mice show an only moderate increase in nutrient signaling to mTORC1, and after one year of life exhibit multiple features of a premature aging phenotype that include prominent senescence in peripheral organs, parenchymal expression of inflammatory and chemo-attractant molecules, increased myeloid inflammation and extensive features of inflammaging. In vivo transplantation and ex vivo functional experiments with bone marrow-derived cells show that myeloid cells are abnormally activated by parenchymal signals evoked from Rragcmut/+ organs, to where myeloid cells extravasate to inflict additional inflammatory damage. Therapeutic suppression of myeloid inflammation in old Rragcmut/+ attenuates features of premature aging and extends longevity. We provide the first genetic link of elevated nutrient – mTORC1 activity and premature aging in mammals, and provide support for a two-component model in which increased nutrient signaling drives parenchymal damage and myeloid inflammation precipitates organ deterioration and accelerated aging.
2024-04-02 | GSE221284 | GEO
Project description:The mechanistic target of rapamycin complex 1 (mTORC1) controls cellular anabolism in response to nutrient sufficiency and growth factor signaling, and genetic and pharmacological inhibition of mTORC1 extends longevity across eukaryotes. Up to date, mouse models to analyze the mechanisms of aging governed by mTORC1 has been limited by detrimental pleiotropic consequences of genetically-increased mTORC1 activity in mice. RragcS74N/+, RragcS74C/+ and RragcT89N/+ knock-in mice endogenously express active mutant variants of RagC, a GTPase that signaling nutrient sufficiency to mTORC1. Rragcmutant/+ mice show an only moderate increase in nutrient signaling to mTORC1, and after one year of life exhibit multiple features of a premature aging phenotype that include prominent senescence in peripheral organs, parenchymal expression of inflammatory and chemo-attractant molecules, increased myeloid inflammation and extensive features of inflammaging. In vivo transplantation and ex vivo functional experiments with bone marrow-derived cells show that myeloid cells are abnormally activated by parenchymal signals evoked from Rragcmut/+ organs, to where myeloid cells extravasate to inflict additional inflammatory damage. Therapeutic suppression of myeloid inflammation in old Rragcmut/+ attenuates features of premature aging and extends longevity. We provide the first genetic link of elevated nutrient – mTORC1 activity and premature aging in mammals, and provide support for a two-component model in which increased nutrient signaling drives parenchymal damage and myeloid inflammation precipitates organ deterioration and accelerated aging.
2024-04-02 | GSE221283 | GEO
Project description:Sarcopenia is an age-associated loss of skeletal muscle mass and strength that increases the risk of disability. Calorie restriction (CR), the consumption of fewer calories while maintaining adequate nutrition, mitigates sarcopenia and many other age-related diseases. To identify potential mechanisms by which CR preserves skeletal muscle integrity during aging, we used mRNA-Seq for deep characterization of gene regulation and mRNA abundance in skeletal muscle of old mice compared with old mice subjected to CR. mRNA-Seq revealed complex CR-associated changes in expression of mRNA isoforms, many of which occur without a change in total message abundance and thus would not be detected by methods other than mRNA-Seq. Functional annotation of differentially expressed genes reveals CR-associated upregulation of pathways involved in energy metabolism and lipid biosynthesis, and downregulation of pathways mediating protein breakdown and oxidative stress, consistent with earlier microarray-based studies. CR-associated changes not noted in previous studies involved downregulation of genes controlling actin cytoskeletal structures and muscle development. These CR-associated changes reflect generally healthier muscle, consistent with CR’s mitigation of sarcopenia. mRNA-Seq generates a rich picture of the changes in gene expression associated with CR, and may facilitate identification of genes that are primary mediators of CR’s effects. Comprehensive survey of mRNA from skeletal muscle of mice subjected to calorie restricted or control diets using deep sequencing
2011-11-22 | E-GEOD-33863 | biostudies-arrayexpress