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Mechanical regulation of the glucocorticoid-sensitive transcriptome in young and aged skeletal muscle

ABSTRACT: Elevated glucocorticoids alter the skeletal muscle transcriptome to induce a myopathy characterized by muscle atrophy, muscle weakness, and decreased metabolic function. These effects are more likely to occur and be more severe in aged muscle. Resistance exercise can blunt development of glucocorticoid myopathy in young muscle, but the potential to blunt the signals initiating myopathy in aged muscle is unknown. To answer this, young (4-month-old) and aged (24-25-month-old) male C57BL/6 mice were randomized to receive either an intraperitoneal (IP) injection of dexamethasone (DEX; 2 mg/kg) or saline as a control. Two hours post-injections, tibialis anterior (TA) muscles of mice were subjected to unilateral high force contractions. Muscles were harvested four hours later. The glucocorticoid- and contraction-sensitive genes were determined by RNA sequencing. The number of glucocorticoid sensitive genes was similar between young and aged muscle. Contractions altered more glucocorticoid-sensitive genes in aged muscle, with this outcome primarily occurring when hormone levels were elevated. Glucocorticoid-sensitive gene programs altered by contractions were primarily related to metabolism in young mice and muscle size regulation and inflammation in aged mice. In silico analysis implied Peroxisome proliferator-activated receptor gamma-1 (PPARG) contributed to the contraction-induced changes in glucocorticoid-sensitive genes in aged muscle. Increasing PPARG expression in the TA of aged mice using Adeno-associated virus serotype 9 partially counteracted the glucocorticoid-induced reduction in Runt-related transcription factor 1 (Runx1) mRNA content, recapitulating the effects observed by contractions. Overall, these data contribute to our understanding of the mechanical regulation of the glucocorticoid transcriptome in aged skeletal muscle.

ORGANISM(S): Mus musculus

PROVIDER: GSE269698 | GEO | 2024/10/28

REPOSITORIES: GEO

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Project description:Belt electrode-skeletal muscle electrical stimulation (B-SES) involves the use of belt-shaped electrodes to simultaneously contract multiple muscle groups. Twitch contractions have been demonstrated to protect against denervation-induced muscle atrophy in rats, possibly via mitochondrial biosynthesis. In this study, we examined whether inducing tetanus contractions with B-SES suppresses muscle atrophy and identified the underlying molecular mechanisms. We evaluated the effects of acute (60 Hz, 5 min) and chronic (60 Hz, 5 min, every alternate day for 1 week) B-SES on the tibialis anterior (TA) and gastrocnemius (GAS) muscles in Sprague Dawley rats using belt electrodes attached to both ankle joints. In acute stimulation, a significant decrease in glycogen content in the left and right TA and GAS was observed, suggesting that B-SES causes simultaneous contractions in multiple muscle groups. B-SES also enhanced p70S6K phosphorylation, an indicator of the mechanistic target of rapamycin complex 1 activity. During chronic stimulations, rats were divided into control (CONT), denervation-induced atrophy (DEN), and DEN+electrically stimulated with B-SES (DEN＋ES) groups. After 7 days of treatment, muscle wet weight (n = 8-11 for each group) and muscle fiber cross-sectional area (CSA, n = 6 for each group) of the TA and GAS muscles were reduced in the DEN and DEN+ES groups compared to those in the CON group. The DEN+ES group showed significantly higher muscle weight and CSA than the DEN group. Although RNA-seq and pathway analysis suggested that mitochondrial and ribosome biogenesis are key events in this phenomenon, mitochondrial content showed no difference. In contrast, ribosomal RNA 28S and 45S (n = 6) levels in the DEN+ES group were higher than those in the DEN group. The mRNA levels of the muscle proteolytic molecules Atrogin-1 and MuRF1 were significantly higher in DEN than in CONT but were suppressed in DEN+ES. In conclusion, tetanic electrical stimulation of both ankles using belt electrodes was effective in preventing denervation-induced atrophy in multiple muscle groups. Unlike twitch contractions, ribosomal biosynthesis plays a key role in tetanic contractions to prevent muscle atrophy.

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Mechanical regulation of the glucocorticoid-sensitive transcriptome in young and aged skeletal muscle

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