Skeletal muscle in aged mice reveals extensive transformation of muscle gene expression (original) (raw)
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Skeletal muscle transcriptome in healthy aging
Nature Communications
Age-associated changes in gene expression in skeletal muscle of healthy individuals reflect accumulation of damage and compensatory adaptations to preserve tissue integrity. To characterize these changes, RNA was extracted and sequenced from muscle biopsies collected from 53 healthy individuals (22–83 years old) of the GESTALT study of the National Institute on Aging–NIH. Expression levels of 57,205 protein-coding and non-coding RNAs were studied as a function of aging by linear and negative binomial regression models. From both models, 1134 RNAs changed significantly with age. The most differentially abundant mRNAs encoded proteins implicated in several age-related processes, including cellular senescence, insulin signaling, and myogenesis. Specific mRNA isoforms that changed significantly with age in skeletal muscle were enriched for proteins involved in oxidative phosphorylation and adipogenesis. Our study establishes a detailed framework of the global transcriptome and mRNA isof...
Exercise-induced gene expression changes in skeletal muscle of old mice
Genomics, 2021
Exercise is believed to be beneficial for skeletal muscle functions across all ages. Regimented exercise is often prescribed as an effective treatment/prophylaxis for age-related loss of muscle mass and functions known as sarcopenia, and plays an important role in the maintenance of mobility and functional independence in the elderly. However, response to exercise changes with aging, with a shift from a predominantly anabolic response resulting in limited gain of muscle strength and endurance. These changes likely reflect age-dependent alterations in transcriptional response underlying the muscular adaptation to exercise. The exact changes in gene expression accompanying exercise, however, are largely unknown, and elucidating them is of a great clinical interest for understanding and optimizing the exercise-based therapies for sarcopenia. In order to characterize the exercise-induced transcriptomic changes in aged muscle, a paired-end RNA sequencing was performed on the rRNA-depleted total RNA extracted from the gastrocnemius muscles of 24 months-old mice after 8 weeks of regimented exercise (exercise group) or no formal exercise program (sedentary group).
Skeletal Muscle
Background As a result of aging, skeletal muscle undergoes atrophy and a decrease in function. This age-related skeletal muscle weakness is known as “sarcopenia”. Sarcopenia is part of the frailty observed in humans. In order to discover treatments for sarcopenia, it is necessary to determine appropriate preclinical models and the genes and signaling pathways that change with age in these models. Methods and results To understand the changes in gene expression that occur as a result of aging in skeletal muscles, we generated a multi-time-point gene expression signature throughout the lifespan of mice and rats, as these are the most commonly used species in preclinical research and intervention testing. Gastrocnemius, tibialis anterior, soleus, and diaphragm muscles from male and female C57Bl/6J mice and male Sprague Dawley rats were analyzed at ages 6, 12, 18, 21, 24, and 27 months, plus an additional 9-month group was used for rats. More age-related genes were identified in rat ske...
Transcriptional profiling of aging in human muscle reveals a common aging signature
PLoS Genetics, 2005
We analyzed expression of 81 normal muscle samples from humans of varying ages, and have identified a molecular profile for aging consisting of 250 age-regulated genes. This molecular profile correlates not only with chronological age but also with a measure of physiological age. We compared the transcriptional profile of muscle aging to previous transcriptional profiles of aging in the kidney and the brain, and found a common signature for aging in these diverse human tissues. The common aging signature consists of six genetic pathways; four pathways increase expression with age (genes in the extracellular matrix, genes involved in cell growth, genes encoding factors involved in complement activation, and genes encoding components of the cytosolic ribosome), while two pathways decrease expression with age (genes involved in chloride transport and genes encoding subunits of the mitochondrial electron transport chain). We also compared transcriptional profiles of aging in humans to those of the mouse and fly, and found that the electron transport chain pathway decreases expression with age in all three organisms, suggesting that this may be a public marker for aging across species.
Mechanisms of Ageing and Development, 2000
The gene expression profile of skeletal muscle from healthy older (62 -75 years old) compared with younger (20-34 years old) men demonstrated elevated expression of genes typical of a stress or damage response, and decreased expression of a gene encoding a DNA repair/cell cycle checkpoint protein. Although the expression of these genes was relatively unaffected by a single bout of resistance exercise in older men, acute exercise altered gene expression in younger men such that post-exercise gene expression in younger men was similar to baseline gene expression in older men. The lack of response of muscle from older subjects to resistance exercise was also apparent in the expression of the inflammatory response gene IL-1b, which did not differ between the age groups at baseline, but increased within 24 h of the exercise bout only in younger subjects. Other genes with potentially important roles in the adaptation of muscle to exercise, specifically in the processes of angiogenesis and cell proliferation, showed a similar response to exercise in older compared with younger subjects. Only one gene encoding the multifunctional, early growth response transcription factor EGR-1, showed an opposite pattern of expression in response to exercise, acutely decreasing in younger and increasing in older subjects. These results may provide a molecular basis for the inherent variability in the response of muscle from older as www.elsevier.com/locate/mechagedev : S 0 0 4 7 -6 3 7 4 ( 0 0 ) 0 0 1 7 8 -0 A.C. Jozsi et al. / Mechanisms of Ageing and De6elopment 120 (2000) 45-56 46 compared with younger individuals to resistance training.
Altered Gene Expression of Muscle Satellite Cells Contributes to Agerelated Sarcopenia in Mice
Current Aging Science, 2019
Background: During aging, muscle tissue undergoes profound changes which lead to a decline in its functional and regenerative capacity. We utilized global gene expression analysis and gene set enrichment analysis to characterize gene expression changes in aging muscle satellite cells. Method: Gene expression data; obtained from Affymetrix Mouse Genome 430 2.0 Array, for 14 mouse muscle satellite cell samples (5 young, 4 middle-aged, and 5 aged), were retrieved from public Gene Expression Omnibus repository. List of differentially expressed genes was generated based on 0.05 multiple-testing-adjusted p-value and 2-fold FC cutoff values. Functional profiling of genes was carried out using PANTHER Classification System. Results: We have found several differentially expressed genes in satellite cells derived from aged mice compared to young ones. The gene expression changes increased progressively with time, and the majority of the differentially expressed genes were upregulated during aging. While the downregulated genes could not be correlated with specific biological processes the upregulated ones could be associated with muscle differentiation-, inflammation-or fibrosis-related processes. The latter two processes encompass the senescence-associated secretory phenotype for satellite cells which alters the tissue microenvironment and contributes to inflammation and fibrosis observed in aging muscle. Conclusion: Our analysis reveals that by altering gene expression pattern and expressing inflammatory mediators and extracellular matrix components, these cells can directly contribute to muscle wasting in aged mice.
Aging Affects the Transcriptional Regulation of Human Skeletal Muscle Disuse Atrophy
PLoS ONE, 2012
Important insights concerning the molecular basis of skeletal muscle disuse-atrophy and aging related muscle loss have been obtained in cell culture and animal models, but these regulatory signaling pathways have not previously been studied in aging human muscle. In the present study, muscle atrophy was induced by immobilization in healthy old and young individuals to study the time-course and transcriptional factors underlying human skeletal muscle atrophy. The results reveal that irrespectively of age, mRNA expression levels of MuRF-1 and Atrogin-1 increased in the very initial phase (2-4 days) of human disuse-muscle atrophy along with a marked reduction in PGC-1a and PGC-1b (1-4 days) and a ,10% decrease in myofiber size (4 days). Further, an age-specific decrease in Akt and S6 phosphorylation was observed in young muscle within the first days (1-4 days) of immobilization. In contrast, Akt phosphorylation was unchanged in old muscle after 2 days and increased after 4 days of immobilization. Further, an age-specific down-regulation of MuRF-1 and Atrogin-1 expression levels was observed following 2 weeks of immobilization, along with a slowing atrophy response in aged skeletal muscle. Neither the immediate loss of muscle mass, nor the subsequent age-differentiated signaling responses could be explained by changes in inflammatory mediators, apoptosis markers or autophagy indicators. Collectively, these findings indicate that the time-course and regulation of human skeletal muscle atrophy is age dependent, leading to an attenuated loss in aging skeletal muscle when exposed to longer periods of immobility-induced disuse.
Microarray Analysis Reveals Novel Features of the Muscle Aging Process in Men and Women
The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2013
To develop a global view of muscle transcriptional differences between older men and women and sex-specific aging, we obtained muscle biopsies from the biceps brachii of young and older men and women and profiled the whole-genome gene expression using microarray. A logistic regression-based method in combination with an intensity-based Bayesian moderated t test was used to identify significant sex-and aging-related gene functional groups. Our analysis revealed extensive sex differences in the muscle transcriptome of older individuals and different patterns of transcriptional changes with aging in men and women. In older women, we observed a coordinated transcriptional upregulation of immune activation, extracellular matrix remodeling, and lipids storage; and a downregulation of mitochondrial biogenesis and function and muscle regeneration. The effect of aging results in sexual dimorphic alterations in the skeletal muscle transcriptome, which may modify the risk for developing musculoskeletal and metabolic diseases in men and women.
PeerJ
Sarcopenia is an age-related disease characterized by the loss of muscle mass and muscle function. A proper understanding of its pathogenesis and mechanisms may lead to new strategies for diagnosis and treatment of the disease. This study aims to discover the underlying genes, proteins, and pathways associated with sarcopenia in both genders. Integrated analysis of microarray datasets has been performed to identify differentially expressed genes (DEGs) between old and young skeletal muscles. Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were then performed to uncover the functions of the DEGs. Moreover, a protein–protein interaction (PPI) network was constructed based on the DEGs. We have identified 41,715 DEGs, including 19 downregulated and 41,696 upregulated ones, in men. Among women, 3,015 DEGs have been found, with 2,874 of them being upregulated and 141 downregulated genes. Among the top up-regulated and d...
Oncotarget, 2018
Aging significantly affects the cardiac muscle (CM) and skeletal muscles (SM). Since the aging process of CM and SM may be different, high throughput RNA sequencing was performed using CM and SM in different age conditions to evaluate the expression profiles of messenger RNA (mRNA), long non-coding RNA (lncRNA), micro RNA (miRNA), and circular (circRNA). Several mRNAs, lncRNAs, and miRNAs were highly expressed and consistently appeared in both ages in one of the two muscle tissues. Gene ontology (GO) annotation described that these genes were required for maintaining normal biological functions of CM and SM tissues. Furthermore, 26 mRNAs, 4 lncRNAs, 22 miRNAs, and 26 circRNAs were differentially expressed during cardiac muscle aging. Moreover, 81 mRNAs, 5 lncRNAs, 79 miRNAs, and 62 circRNAs were differentially expressed during aging of skeletal muscle. When comparing the expression profiles of CM and SM during aging, the senescence process in CM and SM was found to be fundamentally ...