Unknown,Transcriptomics,Genomics,Proteomics

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Skeletal muscle PGC-1a mediates mitochondrial, but not metabolic, changes during calorie restriction.

ABSTRACT: 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.

ORGANISM(S): Mus musculus

SUBMITTER: Marcia Haigis

PROVIDER: E-GEOD-34773 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Skeletal muscle transcriptional coactivator PGC-1α mediates mitochondrial, but not metabolic, changes during calorie restriction.

Finley Lydia W S LW Lee Jaewon J Souza Amanda A Desquiret-Dumas Valérie V Bullock Kevin K Rowe Glenn C GC Procaccio Vincent V Clish Clary B CB Arany Zoltan Z Haigis Marcia C MC

Proceedings of the National Academy of Sciences of the United States of America 20120203 8

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 (ROS) scavenging in skeletal muscle and other tissues, and these processes are thought to be critical to the benefits of CR. PGC-1α is a transcriptional coactivator that regulates mitochondrial function and is induced by CR. Consequently, many of the mitochondrial and metabolic benefits of CR ar ...[more]

PMID: 22308395

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Project description:OBJECTIVE: To understand the molecular pathways underlying the cardiac preconditioning effect of short-term caloric restriction (CR). BACKGROUND: Lifelong CR has been suggested to reduce the incidence of cardiovascular disease through a variety of mechanisms. However, prolonged adherence to a CR life-style is difficult. Here we show how short-term CR protects the mouse heart from ischemia. METHODS: Male 10-12 wk old C57bl/6 mice were randomly assigned to an ad libitum (AL) diet with free access to regular chow, or CR, receiving 30% less food over a period of 7 days (d), prior to myocardial infarction (MI) via permanent coronary ligation. Prior to MI (d8), the left ventricles (LV) of AL and CR mice were collected for Western blot, DNA and microRNA (miR) analyses. In separate groups, infarct size, cardiac hemodynamics and protein abundance of caspase 3 was measured at d2 post-MI. RESULTS: This short-term model of CR was associated with cardio-protection, as evidenced by decreased infarct size (18.5±2.4% vs. 26.6±1.7%, N=10/group; P=0.01). cDNA and miR profiles pre-MI (N=5/group) identified genes modulated by short-term CR to be associated with circadian clock, oxidative stress, immune function, apoptosis, metabolism, angiogenesis, cytoskeleton and extracellular matrix (ECM). Western blots pre-MI revealed CR-associated increases in phosphorylated Akt and GSK3ß, reduced levels of phosphorylated AMPK and mitochondrial related proteins PGC-1?, cytochrome C and cyclooxygenase (COX) IV, with no differences in the levels of phosphorylated eNOS or MAPK (ERK1/2; p38). CONCLUSIONS: Short-term CR for only 7d represents a preconditioning strategy that limits infarct size. It is associated with a unique gene and miR signature, including the activation of specific pro-survival kinases. These findings may have implications for therapeutic use of short-term CR. . Male 12 wk-old C57Bl/6 mice were obtained from Charles River (Montreal, PQ, Canada) and maintained for at least 2 weeks before experimentation. Animals were randomly assigned to AL, CR and Lira groups with no initial differences in body weights. AL group mice were allowed ad libitum diet. Lira group mice were injected with Liraglutide (Glucagon-like peptide-1 agonist) at a dose of 200 µg/Kg i.p., twice daily for 7 days which is a mild weight-loss inducing dose and had access to ad libitum food and water. CR group mice were put on a Caloric restriction diet (30% less than normal ad libitum caloric intake) for 7 days to induce weight loss comparable to Lira group mice. Mice for CR and AL were individually caged and their food intake was measured everyday between 10-11 am for 1 week to calculate the average daily food intake. CR mice were fed 30% less than the calculated mean daily AL food consumption. CR cages were inspected daily for any remaining food, and transferred to a new cage every day. For CR group, pre-weighed mouse chow pellets were placed in cages between 10-11 am every day. Body weights were recorded between 10-11 am before and after the 7 day study period. For pre-ischemic assessments, animals (n=5/group/assessment) were sacrificed on day-8 (pre-MI), hearts were immediately extracted, washed in sterile phosphate-buffered saline (PBS), with LV free walls dissected, snap frozen in liquid nitrogen and stored at -80o C.

Project description:This experiment was conducted to identify target genes of the microRNA-499 in skeletal muscle of transgenic mice that overexpressed miR-499. The following abstract from the submitted manuscript describes the major findings of this work. Coupling of mitochondrial function and skeletal muscle fiber type by a miR-499/Fnip1/AMPK circuit. Jing Liu, Xijun Liang, Danxia Zhou, Ling Lai, Tingting Fu, Yan Kong, Qian Zhou, Rick B. Vega, Min-Sheng Zhu, Daniel P. Kelly, Xiang Gao, and Zhenji Gan. Upon adaption of skeletal muscle to physiological and pathophysiological stimuli, muscle fiber type and mitochondrial function are coordinately regulated. Recent studies have identified pathways involved in control of contractile proteins of oxidative type fibers. However, the mechanism for coupling of mitochondrial function to muscle contractile machinery during fiber type transition remains unknown. Here, we show that the expression of the genes encoding type I myosins, Myh7/Myh7b and their intronic miR-208b/miR-499 parallels mitochondrial function during fiber type transitions. Using in vivo approaches in mice, we found that miR-499 drives a PGC-1a-dependent mitochondrial oxidative metabolism program to match shifts in slow-twitch muscle fiber composition. Mechanistically, miR-499 directly targets Fnip1, a known AMP-activated protein kinase (AMPK)-interacting protein that negatively regulates AMPK, a known activator of PGC-1a. Inhibition of Fnip1 reactivated AMPK/PGC-1a signaling and mitochondrial function in myocytes. Restoration of the expression of miR-499 in the mdx mouse model of Duchenne muscular dystrophy (DMD) reduced the severity of DMD. Thus, we have identified a miR-499/Fnip1/AMPK circuit that can serve as a mechanism to couple muscle fiber type and mitochondrial function. Keywords: muscle, contractile fiber type, mitochondrial function, microRNA, gene regulation RNA from three wild-type (non-transgenic (NTG)) and three miR-499 overexpressing (MCK-miR-499) mice was analyzed. three replicates of each are provided.

Project description:With the population of older and overweight individuals on the rise in the Western world, there is an ever greater need to slow the aging processes and reduce the burden of age-associated chronic disease that would significantly improve the quality of human life and reduce economic costs. Caloric restriction (CR), is the most robust and reproducible intervention known to delay aging and to improve healthspan and lifespan across species (1); however, whether this intervention can extend lifespan in humans is still unknown. Here we report that rats and humans exhibit similar responses to long-term CR at both the physiological and molecular levels. CR induced broad phenotypic similarities in both species such as reduced body weight, reduced fat mass and increased the ratio of muscle to fat. Likewise, CR evoked similar species-independent responses in the transcriptional profiles of skeletal muscle. This common signature consisted of three key pathways typically associated with improved health and survival: IGF-1/insulin signaling, mitochondrial biogenesis and inflammation. To our knowledge, these are the first results to demonstrate that long-term CR induces a similar transcriptional profile in two very divergent species, suggesting that such similarities may also translate to lifespan-extending effects in humans as is known to occur in rodents. These findings provide insight into the shared molecular mechanisms elicited by CR and highlight promising pathways for therapeutic targets to combat age-related diseases and promote longevity in humans. Male Fisher 344 rats (n=54) were randomly assigned to two groups at 2 months of age. One group was kept ad libitum (AL) fed throughout their lifespan while the calorie restriction (CR) group was progressively brought down to a 40% CR. All animals were fed a NIH-31 standard chow (Harlan Teklad, Indianapolis, IN, USA). Rats were singly housed in an environmentally controlled vivarium with unlimited access to water and a controlled photoperiod (12 hr. light;12 hr. dark). Body weights and food intake were recorded biweekly. All rats were maintained between 68-72M-BM-0F according to animal protocols and NIH guidelines. Total RNA was extracted from the vastus lateralis skeletal muscle using Trizol Reagent (Invitrogen, Carlsbad, CA) following the manufacturerM-bM-^@M-^Ys instructions, n=5 from each group. Total RNA samples were biotin labeled and hybridized to RatRef-12 v1 Gene Expression beadchips (Illumina, San Diego, CA) following Illumina protocols. Arrays were washed and scanned using an Illumina BeadArray 500GX reader. Microarray florescent signals were extracted using the Illumina GenomeStudio Gene Expression software(v1.6.0) and any spots at or below the background were filtered using an Illumina detection p-value of 0.02 and above. The natural log of all remaining scores were used to find the avg and std of each array and the z-score normalization was calculated . Correlation analysis, sample clustering analysis and principal component analysis include all of probes are performed to identify/exclude any possible outliners. The resulting dataset was next analyzed with DIANE 6.0, a spreadsheet based microarray analysis program. Gene set enrichment analysis use gene expression values or gene expression change values for all of the genes in the microarray. Parametric analysis of gene set enrichment (PAGE) was used [pubmed 20682848] for gene set analysis. Gene Sets include the MSIG database [Link], Gene Ontology Database [Link], GAD human disease and mouse phenotype gene sets [pubmed: 20092628] were used to explore functional level changes.

Dataset Information

Skeletal muscle PGC-1a mediates mitochondrial, but not metabolic, changes during calorie restriction.

Publications

Skeletal muscle transcriptional coactivator PGC-1α mediates mitochondrial, but not metabolic, changes during calorie restriction.

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