ACTN3 genotype influences androgen response in skeletal muscle
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ABSTRACT:
PROVIDER: PRJNA1272536 | ENA |
REPOSITORIES: ENA
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Project description:Androgens act through androgen receptor (AR) to maintain muscle mass. Evidence suggests that this pathway is influenced by ACTN3 (α-actinin-3) - “the Gene for Speed”. Given that one in 5 people worldwide lack α-actinin-3, it is possible they may respond to androgens differently. In this study, we show that α-actinin-3 deficiency decreases AR in skeletal muscles of mice and humans (in males and females), and that AR levels positively correlate with α-actinin-3 expression in a dosage dependent manner. α-Actinin-3 deficiency exacerbates gastrocnemius muscle mass loss with androgen deprivation in male mice, and stunts the muscle growth response to dihydrotestosterone at the onset of puberty in female mice. This is mediated by differential activation of pathways regulating amino acid metabolism, intracellular transport, autophagy, mitochondrial activity, MAPK and calcineurin signalling, which may be driven by 7 key genes that are both androgen sensitive and α-actinin-3-dependent in expression. Our results highlight a role for α-actinin-3 in the regulation of muscle mass and suggest that ACTN3 is a genetic modifier of androgen action in skeletal muscle.
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Project description:Androgens exert their effects primarily by binding to the androgen receptor (AR), a ligand-dependent nuclear receptor. While androgens have anabolic effects on skeletal muscle, previous studies reported that AR functions in myofibers to regulate skele- tal muscle quality, rather than skeletal muscle mass. Therefore, the anabolic effects of androgens are exerted via nonmyofiber cells. In this context, the cellular and molecular mechanisms of AR in mesenchymal progenitors, which play a crucial role in maintaining skeletal muscle homeostasis, remain largely unknown. In this study, we demonstrated expression of AR in mesenchymal progenitors and found that targeted AR ablation in mesenchymal progenitors reduced limb muscle mass in mature adult, but not young or aged, male mice, although fatty infiltration of muscle was not affected. The absence of AR in mesenchymal progenitors led to remarkable perineal muscle hypotrophy, regard- less of age, due to abnormal regulation of transcripts associated with cell death and extracellular matrix organization. Additionally, we revealed that AR in mesenchymal progenitors regulates the expression of insulin-like growth factor 1 (Igf1) and that IGF1 administration prevents perineal muscle atrophy in a paracrine manner. These findings indicate that the anabolic effects of androgens regulate skeletal muscle mass via, at least in part, AR signaling in mesenchymal progenitors.
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Project description:Skeletal Muscle Transcriptomics
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Project description:<p>Glycolytic potential (GP) is an important index for evaluating meat quality in the pig industry, since high muscle glycogen content generally leads to rapid postmortem glycolysis, which contributes to low meat quality. However, there are few researches to elucidate the genetic mechanisms underlie pig skeletal muscle glycolysis. This study represents the first investigation into the mechanisms of skeletal muscle glycolysis, integrating gene expression and metabolic profiles in Jinhua (JH) and Landrace × Yorkshire (LY) pigs across three growth periods (1, 90 and 180 days after postpartum) using multi-omics techniques. The results revealed that JH pigs exhibit lower intramuscular glycogen content than LY pigs throughout the growth period (p < 0.05). Increased phosphorylated glycogen synthase (p-GS) expression indicated reduced glycogenesis capacity in JH pigs. Transcriptomic analysis demonstrated that differential expression genes (DEGs) between JH and LY pigs were significantly enriched in glycolysis, glycogenesis, and the TCA cycle, with these pathways exhibiting inhibition in JH pigs. Metabolomic analysis identified that flavor-related metabolites such as lipids and amino acids were increased but carbohydrate metabolites were decreased in JH pigs relative to LY pigs. Through integrated analysis between genes and metabolites, we identified VASH1 as a key regulator of skeletal muscle glycolysis. Mechanistically, VASH1 knockdown promoting glucose metabolism through enhanced glycolysis and glycogenesis through AMPK signaling pathway in myoblasts. Our findings provided novel insights into the genetic basis of meat quality and identify VASH1 as a potential target for genetic selection to improve pork quality.</p>
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Project description:Loss of muscle mass and function—a hallmark of skeletal muscle aging—is known as sarcopenia. Moreover, mammalian aging is reportedly driven by loss of epigenetic information. However, the effect of epigenetic alterations on skeletal muscle homeostasis is unknown. In this study, we show that chronic elevation of global DNA methylation results in a myopathy-like phenotype and age-related changes in skeletal muscle. Overexpression of muscle de novo methyltransferase 3a (Dnmt3a) increased central nucleus-positive myofibers, predominantly in fast-twitch myofibers, and shifted muscle fiber type to stress-resistant slow-twitch myofibers, accompanied by upregulation of chemokine and immune system-related genes and reduced basal autophagy in skeletal muscle. Dnmt3a overexpression reduced muscle androgen receptor signaling, decreased muscle mass and strength, and impaired tolerance to endurance exercise with age. Network analysis identified Akt1 as a potential hub gene. Dnmt3a expression reduced sensitivity to starvation-induced muscle atrophy by suppressing the FoxO-regulated autophagy and ubiquitin–proteasome systems. These data suggest that increased global DNA methylation disrupts skeletal muscle homeostasis, promotes age-related decline in muscle function, and reduces muscle plasticity.
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Project description:Skeletal muscle actin mice (Crawford et al., (2002) Mol Cell Biol 22, 5587) were crossed with cardiac actin transgenic mice (termed "ACTC^Coco" or "Coco" for short), to produce mice that had cardiac actin instead of skeletal muscle actin in their skeletal muscles (termed "ACTC^Co/KO" or for short "Coco/KO"). Microarray analysis using the Illumina mouse-6 v1.1 expression beadchip was performed on RNA extraced from the soleus muscle of Coco/KO mice and wildtype mice, to confirm the swith in actin isoform expression, and to determine what other differences might exist between wildtype mice and the Coco/KO mice. Keywords: genetic modification 3 RNA samples (each being the pool of two individual samples extracted from different soleus muscles from different individual mice) per genotype (either wildtype or Coco/KO) were used. The total 6 RNA samples were processed using an Illumina mouse-6 v1.1expression beadchip and then the differentially expressed genes determined.
2009-05-24 | E-GEOD-12882 | biostudies-arrayexpress