Our understanding of the molecular mechanisms underlying adaptations to resistance exercise remains elusive despite the significant biological and clinical relevance. We developed a novel voluntary mouse weightlifting model, which elicits squat‐like activities against adjustable load during feeding, to investigate the resistance exercise‐induced contractile and metabolic adaptations. RNAseq analysis revealed that a single bout of weightlifting induced significant transcriptome responses of genes that function in posttranslational modification, metabolism, and muscle differentiation in recruited skeletal muscles, which were confirmed by increased expression of fibroblast growth factor‐inducible 14 (Fn14), Down syndrome critical region 1 (Dscr1) and Nuclear receptor subfamily 4, group A, member 3 (Nr4a3) genes. Long‐term (8 weeks) voluntary weightlifting training resulted in significantly increases of muscle mass, protein synthesis (puromycin incorporation in SUnSET assay) and mTOR pathway protein expression (raptor, 4e‐bp‐1, and p70S6K proteins) along with enhanced muscle power (specific torque and contraction speed), but not endurance capacity, mitochondrial biogenesis, and fiber type transformation. Importantly, weightlifting training profound improved whole‐body glucose clearance and skeletal muscle insulin sensitivity along with enhanced autophagy (increased LC3 and LC3‐II/I ratio, and decreased p62/Sqstm1). These data suggest that resistance training in mice promotes muscle adaptation and insulin sensitivity with simultaneous enhancement of autophagy and mTOR pathway.
Osteoporosis is a common, increasingly prevalent, global health burden characterized by low bone mineral density (BMD) and increased risk of fracture. Despite its significant impact on human health, there is currently a lack of highly effective treatments free of side effects for osteoporosis. Therefore, a major goal in the field is to identify new drug targets. Genetic discovery has been shown to be effective in the unbiased identification of novel drug targets and genome-wide association studies (GWASs) have begun to provide insight into genetic basis of osteoporosis. Over the last decade, GWASs have led to the identification of ~100 loci associated with BMD and other bone traits related to risk of fracture. However, there have been limited efforts to identify the causal genes underlying the GWAS loci or the mechanisms by which GWAS loci alter bone physiology. In this review, we summarize the current state of the field and discuss strategies for causal gene discovery and the evidence that the novel genes underlying GWAS loci are likely to be a new source of drug targets.
Highlights d Combining networks and GWAS data provides insights into the genetics of BMD d A co-expression module with ''core-like'' characteristics is identified for BMD d Four genes are identified as likely causal genetic drivers of BMD in humans
Parental health influences embryonic development and susceptibility to disease in the offspring. We investigated whether maternal voluntary running during gestation could protect the offspring from the adverse effects of maternal or paternal high-fat diet (HF) in mice. We performed transcriptomic and whole-genome DNA methylation analyses in female offspring skeletal muscle as well as targeted DNA methylation analysis of the peroxisome proliferator-activated receptor γ coactivator-1α (Pgc-1α) promoter in the both male and female adult offspring. Maternal HF resulted in impaired metabolic homeostasis in male offspring at 9 months of age, while both male and female offspring were negatively impacted by paternal HF. Maternal exercise during gestation completely mitigated these metabolic impairments. Female adult offspring from obese male or female parent had skeletal muscle transcriptional profiles enriched in genes regulating inflammation and immune responses, whereas maternal exercise resulted in a transcriptional profile similar to offspring from normal chow fed parents. Maternal HF, but not paternal HF, resulted in hypermethylation of the Pgc-1α promoter at CpG -260, which was abolished by maternal exercise. These findings demonstrate the negative consequences of maternal and paternal HF for the offspring's metabolic outcomes later in life possibly through different epigenetic mechanisms, and maternal exercise during gestation mitigates the negative consequences.
Our understanding of the genetic control of bone strength has relied mainly on estimates of bone mineral density. Here we have mapped genetic factors that influence femoral and tibial microarchitecture using high‐resolution x‐ray computed tomography (8‐μm isotropic voxels) across a family of 61 BXD strains of mice, roughly 10 isogenic cases per strain and balanced by sex. We computed heritabilities for 25 cortical and trabecular traits. Males and females have well‐matched heritabilities, ranging from 0.25 to 0.75. We mapped 16 genetic loci most of which were detected only in females. There is also a bias in favor of loci that control cortical rather than trabecular bone. To evaluate candidate genes, we combined well‐established gene ontologies with bone transcriptome data to compute bone‐enrichment scores for all protein‐coding genes. We aligned candidates with those of human genome‐wide association studies. A subset of 50 strong candidates fell into three categories: (1) experimentally validated genes already known to modulate bone function (Adamts4, Ddr2, Darc, Adam12, Fkbp10, E2f6, Adam17, Grem2, Ifi204); (2) candidates without any experimentally validated function in bone (eg, Greb1, Ifi202b), but linked to skeletal phenotypes in human cohorts; and (3) candidates that have high bone‐enrichment scores, but for which there is not yet any functional link to bone biology or skeletal system disease (including Ifi202b, Ly9, Ifi205, Mgmt, F2rl1, Iqgap2). Our results highlight contrasting genetic architecture between sexes and among major bone compartments. The alignment of murine and human data facilitates function analysis and should prove of value for preclinical testing of molecular control of bone structure. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
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