Project description:Resveratrol in high doses has been shown to extend lifespan in some studies in invertebrates and to prevent early mortality in mice fed a high-fat diet. We fed mice from middle age (14-months) to old age (30-months) either a control diet, a low dose of resveratrol (4.9 mg kg-1 day-1), or a calorie restricted (CR) diet and examined genome-wide transcriptional profiles. We report a striking transcriptional overlap of CR and resveratrol in heart, skeletal muscle and brain. Both dietary interventions inhibit gene expression profiles associated with cardiac and skeletal muscle aging. Gene expression profiling suggests that both CR and resveratrol may retard some aspects of aging through alterations in chromatin structure and transcription. Resveratrol, at doses that can be readily achieved in humans, fulfills the definition of a dietary compound that mimics some aspects of CR. Experiment Overall Design: Heart, neocortex tissue, and gastrocnemius muscle was collected from young and old mice at 5 and 30 months of age, respectively; mice were subjected to either a calorie restricted diet or a control diet supplemented with resveratrol
Project description:In utero undernutrition is associated with obesity and insulin resistance, although its effect on skeletal muscle remains poorly defined. We report that, in mice, adult offspring from undernourished dams have decreased energy expenditure, decreased skeletal muscle mitochondrial content, and altered energetics in isolated mitochondria and permeabilized muscle fibers. Strikingly, when these mice are put on a 40% calorie restricted diet they lose half as much weight as calorie restricted controls. Our results reveal for the first time that in utero undernutrition alters metabolic physiology having a profound effect on skeletal muscle energetics and response to calorie restriction in adulthood. We have used a mouse model of low birth weight generated through 50% food restriction of mouse dams during the third week of gestation. We have studied in utero food restricted offspring and control offspring that were not food restricted in utero in both the ad libitum and calorie restricted states. Gene expression profiling was performed on tibialis anterior muscle from 8 mice per group, pooled in pairs.
Project description:In utero undernutrition is associated with obesity and insulin resistance, although its effect on skeletal muscle remains poorly defined. We report that, in mice, adult offspring from undernourished dams have decreased energy expenditure, decreased skeletal muscle mitochondrial content, and altered energetics in isolated mitochondria and permeabilized muscle fibers. Strikingly, when these mice are put on a 40% calorie restricted diet they lose half as much weight as calorie restricted controls. Our results reveal for the first time that in utero undernutrition alters metabolic physiology having a profound effect on skeletal muscle energetics and response to calorie restriction in adulthood.
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
Project description:Sarcopenia is the age-induced, progressive loss of skeletal muscle mass and function, which is accompanied by reduced muscle performance. Individuals with sarcopenia often become bedridden or dependent on a wheelchair, leading to decreased quality of life. In this study, to better understand changes in skeletal muscle during sarcopenia, we performed a microarray analysis of skeletal muscle in young (13-week-old) and aged (26-month-old) mice. The microarray data shows that expression of the enzymes related to glucose and polyamine metabolism were decreased in aged mice compared with young mice.
Project description:We investigated age-related changes in the transcriptional profile of skeletal muscle in 5 month old (young) and 25 month old (old) C57BL/6NHsd mice using high density oligonucleotide arrays (22,690 transcripts probed). We identified 712 transcripts that are differentially expressed in young (5 month old) and old (25-month old) mouse skeletal muscle. Caloric restriction (CR) completely or partially reversed 87% of the changes in expression. Examination of individual genes revealed a transcriptional profile indicative of increased p53 activity in the older muscle. To determine whether the increase in p53 activity is associated with transcriptional activation of apoptotic targets, we performed RT-PCR on four well known mediators of p53-induced apoptosis: puma, noxa, tnfrsf10b and bok. Expression levels for these proapoptotic genes increased significantly with age (P<0.05), while CR significantly lowered expression levels for these genes as compared to control fed old mice (P<0.05). Age-related induction of p53-related genes was observed in multiple tissues, but was not observed in SOD2+/- and GPX4+/- mice, suggesting that oxidative stress does not mediate the observed age-related increase in expression. Western blot analysis confirmed that protein levels for both p21 and GADD45a, two established transcriptional targets of p53, were higher in the older muscle tissue. These observations support a role for p53-mediated apoptotic activity in mammalian aging. Keywords: aging, calorie restriction, muscle, p53
Project description:Time-restricted eating is emerging as a promising dietary intervention that prevents cardiometabolic disease; however, the molecular mechanisms remain largely unknown. It is generally thought that time-restricted feeding-as it is known in animal studies-reprograms circadian rhythms in peripheral organs including skeletal muscle. Recent studies reported that peripheral organs entrain to time-restricted feeding in a highly diverse tissue-specific manner, which is indicated by the kinetics of the circadian clock in peripheral organs, transcriptome and metabolome. A discrepancy is found in the circadian coherence between rhythmic transcripts and rhythmic metabolites, suggesting the presence of additional regulation at the proteome level. To explore the landscape of rhythmic proteins in skeletal muscle from time-restricted fed mice, we sampled 50 mouse tibialis anterior muscle tissues from 11-week-old C57BL/6J female mice. These mice had been fed day time-restricted feeding for 3 weeks, during which food was accessible between Zeitgeber time (ZT) 0 h and ZT 12 h. Samples were dissected and snap-frozen in liquid nitrogen every two hours starting from ZT0 of the first day to ZT0 of the third day. This sampling scheme covers two complete day/night cycles and has two biological replicates per time point for a total of 25 time points. Next, we performed mass spectrometry-based parallel accumulation–serial fragmentation combined with data-independent acquisition (diaPASEF) quantitative proteomics to analyze these mouse skeletal muscle tissues. Together, we have generated a dataset that provide insights into circadian rhythms of skeletal muscle under the regulation of time-restricted feeding in mice.
Project description:Calorie restriction is a major intervention consistently demonstrated to retard aging and delay age-associated diseases. A novel micronutrient blend, a putative calorie restriction mimetic, was developed based on a screening tool we previously described. Whole transcriptomic analysis was examined in brain cortex, skeletal muscle and heart in three groups of mice: old controls (30 months), old + calorie restriction and old + novel micronutrient blend. The micronutrient blend elicited transcriptomic changes in a manner similar to those in the calorie-restricted group and unique from those in the control group. Subgroup analysis revealed that nuclear hormone receptor, proteasome complex and angiotensinogen genes, all of which are known to be directly related to the aging process, were the most affected by the micronutrient blend and by calorie restriction. Thus, these three genes may be considered master regulators of the favorable effects of calorie restriction and of the micronutrient blend. Based on the calorie restriction mimetic effects on transcriptomics, it was hypothesized that the micronutrient blend would promotes longevity and vitality. To test this hypothesis, a functional analysis in C. Elegans was used to examine the effects of the micronutrient blend on longevity and biomarkers of vitality. Results indicate that feeding C. Elegans the micronutrient blend increased longevity as well as vitality. Further studies are required to confirm that the calorie restriction mimicking benefits described here are elicited by the micronutrient blend in humans.