Influence of metformin treatment during five days of bed rest and recovery in older adults
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE224900 | GEO | 2023/11/22
REPOSITORIES: GEO
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Project description:Muscle atrophy is one of the main deleterious consequences of physical inactivity. Bed rest represents a unique model of physical inactivity and results in main changes in muscle metabolic function. However, our knowledge on the detrimental effects of bed rest still needs clarification. The aim of this study was to decipher the mechanisms involved in disuse muscle atrophy and the effects of different countermeasures in healthy men. A cross-over trial was designed, with each trial consisting in a 7-day ambulatory control period for baseline data collection, followed by 21 days head-down tilt bed rest with or without resistive vibration exercise only or combined with nutritional (protein) supplement as countermeasures. The changes in the Vastus lateralis muscle proteome collected in the eight volunteers were characterized using mass spectrometry-based label-free quantitative proteomics.
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Project description:Short-term bed rest is used to simulate muscle disuse in humans. In our previous reports, we found that 5d of bed rest induced a ~4% loss of skeletal muscle mass in OLD (60-79 y) but not YOUNG (18-28 y) subjects. Identifying muscle transcriptional events in response to bed rest and age-related differences will help identify therapeutic targets to offset muscle loss in vulnerable older adult populations. Skeletal muscle dysregulation during bed rest in the old may be driven by alterations in molecules related to fibrosis, inflammation, and cell adhesion. This information may aide in the development of mechanistic-based therapies to combat muscle atrophy during short-term disuse. Short-term muscle disuse is also characterized by skeletal muscle insulin resistance, though this response is divergent across subjects. The mechanisms regulating inactivity-induced insulin resistance between populations that are more or less susceptible to disuse-induced insulin resistance are not known, and delineated by age. High Susceptibility participants were uniquely characterized with muscle gene responses described by a decrease in pathways responsible for lipid uptake and oxidation, decreased capacity for triglyceride export (APOB), increased lipogenesis (i.e., PFKFB3, FASN), and increased amino acid export (SLC43A1).
2019-02-18 | GSE113165 | GEO
Project description:Evidence from clinical trials and observational studies suggests that both progressive resistance training (PRT) and metformin delay a variety of age-related morbidities. Previously, we completed a clinical trial testing the effects of 14 weeks of PRT + metformin (metPRT) compared to PRT with placebo (plaPRT) on muscle hypertrophy in older adults. We found that metformin blunted PRT-induced muscle hypertrophic response. To understand potential mechanisms underlying the inhibitory effect of metformin on PRT, we analyzed the muscle transcriptome in 23 metPRT and 24 plaPRT participants. PRT significantly increased expression of genes involved in extracellular matrix remodeling pathways, and downregulated RNA processing pathways in both groups, however, metformin blunted the number of differentially expressed genes within these pathways compared to plaPRT. Pathway analysis showed that genes unique to metPRT modulated aging-relevant pathways, such as cellular senescence and autophagy. Differentially expressed genes from baseline biopsies in older adults compared to resting muscle from young volunteers were reduced following PRT in plaPRT and were further reduced in metPRT. We suggest that although metformin may blunt pathways induced by PRT to promote muscle hypertrophy, adjunctive metformin during PRT may have beneficial effects on aging-associated pathways in muscle from older adults.
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Project description:Older individuals subjected to complete bed rest for 10 days were randomized to a complete nutritional supplement with or without hydroxymethyl butyrate (HMB). Muscle biopsies from the vastus lateralis were obtained immediately prior and at the conclusion of the bed rest. RNA-sequencing was performed to determine the gene expression changes associated with bed rest. Marked decrease in the expression of genes associated with mitochondrial energy metabolism including fatty acid oxidation, TCA cycle and the electron transport chain was observed with bed rest. These effects were partly mitigated in the subjects provided the nutritional supplement with HMB.
2019-11-01 | GSE130722 | GEO
Project description:Older individuals were subjected to complete bed rest for 10 days. Muscle biopsies from the vastus lateralis were obtained immediately prior and at the conclusion of the bed rest. RNA-sequencing was performed to determine the gene expression changes associated with bed rest. Marked decrease in the expression of genes associated with mitochondrial energy metabolism including fatty acid oxidation, TCA cycle and the electron transport chain was observed. Upstream regulator analysis revealed that many of these genes are downstream targets of the transcription factors PPAR, ERR and PGC-1alpha.
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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.
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Project description:Administration of metformin increases healthspan and lifespan in model systems and evidence from clinical trials and observational studies suggests that metformin delays a variety of age-related morbidities. Although metformin has been shown to modulate multiple biological pathways at the cellular level, these pleiotropic effects of metformin on the biology of human aging have not been studied. We studied ~70-year-old participants (n=14), in a randomized, double-blind, placebo-controlled, crossover trial in which they were treated with 6 weeks each of metformin and placebo. Following each treatment period, skeletal muscle and subcutaneous adipose tissue biopsies were obtained, and a mixed-meal challenge test was performed. As expected, metformin therapy lowered 2-hour glucose, insulin AUC, and insulin secretion compared to placebo. Using FDR<0.05, 647 genes were differentially expressed in muscle and 146 genes were differentially expressed in adipose tissue. Both metabolic and non-metabolic pathways were significantly influenced, including pyruvate metabolism and DNA repair in muscle and PPAR & SREBP signaling, mitochondrial fatty acid oxidation and collagen trimerization in adipose. While each tissue had, a signature reflecting its own function, we identified a cascade of predictive upstream transcriptional regulators, including mTORC1, MYC, TNF, TGFß1 and miRNA-29b, that may explain tissue-specific transcriptomic changes in response to metformin treatment. This study provides the first evidence that, in older adults, metformin has metabolic and non-metabolic effects linked to aging. These data can inform the development of biomarkers for the effects of metformin, and potentially other drugs, on key aging pathways. Key words: Aging, biguanides, gene expression, metabolism, upstream regulators
2017-12-12 | GSE107894 | GEO
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