Dataset Information

Insulin/IGF1 signalling mediates the effects of ?₂ -adrenergic agonist on muscle proteostasis and growth.

ABSTRACT:

Background

Stimulation of ?₂ -adrenoceptors can promote muscle hypertrophy and fibre type shift, and it can counteract atrophy and weakness. The underlying mechanisms remain elusive.

Methods

Fed wild type (WT), 2-day fasted WT, muscle-specific insulin (INS) receptor (IR) knockout (M-IR^-/- ), and MKR mice were studied with regard to acute effects of the ?₂ -agonist formoterol (FOR) on protein metabolism and signalling events. MKR mice express a dominant negative IGF1 receptor, which blocks both INS/IGF1 signalling. All received one injection of FOR (300 ?g kg^-1 subcutaneously) or saline. Skeletal muscles and serum samples were analysed from 30 to 240 min. For the study of chronic effects of FOR on muscle plasticity and function as well as intracellular signalling pathways, fed WT and MKR mice were treated with formoterol (300 ?g kg^-1 day^-1 ) for 30 days.

Results

In fed and fasted mice, one injection of FOR inhibited autophagosome formation (LC3-II content, 65%, P ? 0.05) that was paralleled by an increase in serum INS levels (4-fold to 25-fold, P ? 0.05) and the phosphorylation of Akt (4.4-fold to 6.5-fold, P ? 0.05) and ERK1/2 (50% to two-fold, P ? 0.05). This led to the suppression (40-70%, P ? 0.05) of the master regulators of atrophy, FoxOs, and the mRNA levels of their target genes. FOR enhanced (41%, P ? 0.05) protein synthesis only in fed condition and stimulated (4.4-fold to 35-fold, P ? 0.05) the prosynthetic Akt/mTOR/p70S6K pathway in both fed and fasted states. FOR effects on Akt signalling during fasting were blunted in both M-IR^-/- and MKR mice. Inhibition of proteolysis markers by FOR was prevented only in MKR mice. Blockade of PI3K/Akt axis and mTORC1, but not ERK1/2, in fasted mice also suppressed the acute FOR effects on proteolysis and autophagy. Chronic stimulation of ?₂ -adrenoceptors in fed WT mice increased body (11%, P ? 0.05) and muscle (15%, P ? 0.05) growth and downregulated atrophy-related genes (30-40%, P ? 0.05), but these effects were abolished in MKR mice. Increases in muscle force caused by FOR (WT, 24%, P ? 0.05) were only partially impaired in MKR mice (12%, P ? 0.05), and FOR-induced slow-to-fast fibre type shift was not blocked at all in these animals. In MKR mice, FOR also restored the lower levels of muscle SDH activity to basal WT values and caused a marked reduction (57%, P ? 0.05) in the number of centrally nucleated fibers.

Conclusions

NS/IGF1 signalling is necessary for the anti-proteolytic and hypertrophic effects of in vivo ?₂ -adrenergic stimulation and appears to mediate FOR-induced enhancement of protein synthesis. INS/IGF1 signalling only partially contributes to gain in strength and does not mediate fibre type transition induced by FOR.

SUBMITTER: Goncalves DA

PROVIDER: S-EPMC6463755 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Insulin/IGF1 signalling mediates the effects of β<sub>2</sub> -adrenergic agonist on muscle proteostasis and growth.

Gonçalves Dawit A DA Silveira Wilian A WA Manfredi Leandro H LH Graça Flávia A FA Armani Andrea A Bertaggia Enrico E O Neill Brian T BT Lautherbach Natalia N Machado Juliano J Nogara Leonardo L Pereira Marcelo G MG Arcidiacono Diletta D Realdon Stefano S Kahn C Ronald CR Sandri Marco M Kettelhut Isis C IC Navegantes Luiz Carlos C LCC

Journal of cachexia, sarcopenia and muscle 20190401 2

<h4>Background</h4>Stimulation of β<sub>2</sub> -adrenoceptors can promote muscle hypertrophy and fibre type shift, and it can counteract atrophy and weakness. The underlying mechanisms remain elusive.<h4>Methods</h4>Fed wild type (WT), 2-day fasted WT, muscle-specific insulin (INS) receptor (IR) knockout (M-IR<sup>-/-</sup> ), and MKR mice were studied with regard to acute effects of the β<sub>2</sub> -agonist formoterol (FOR) on protein metabolism and signalling events. MKR mice express a domi ...[more]

PMID: 30932373

Similar Datasets

Project description:Rodent studies highlight enhancement of glucose tolerance and insulin sensitivity as potential clinically relevant effects of chronic beta2 -agonist treatment. However, the doses administered to rodents are not comparable with the therapeutic doses used for humans. Thus, we investigated the physiological effects of prolonged beta2 -agonist treatment at inhaled doses resembling those used in respiratory diseases on insulin-stimulated whole-body glucose disposal and putative mechanisms in skeletal muscle and adipose tissue of healthy men. Utilizing a randomized placebo-controlled parallel-group design, we assigned 21 healthy men to 4 weeks daily inhalation of terbutaline (TER; 4 mg × day-1 , n = 13) or placebo (PLA, n = 8). Before and after treatments, we assessed subjects' whole-body insulin-stimulated glucose disposal and body composition, and collected vastus lateralis muscle and abdominal adipose tissue biopsies. Glucose infusion rate increased by 27% (95% CI: 80 to 238 mg × min-1 , P = 0.001) in TER, whereas no significant changes occurred in PLA (95% CI: -37 to 195 mg × min-1 , P = 0.154). GLUT4 content in muscle or adipose tissue did not change, nor did hexokinase II content or markers of mitochondrial volume in muscle. Change in lean mass was associated with change in glucose infusion rate in TER (r = 0.59, P = 0.03). Beta2 -agonist treatment in close-to-therapeutic doses may augment whole-body insulin-stimulated glucose disposal in healthy young men and part of the change is likely to be explained by muscle hypertrophy. These findings highlight the therapeutic potential of beta2 -agonists for improving insulin sensitivity. KEY POINTS: While studies in rodents have highlighted beta2 -agonists as a means to augment insulin sensitivity, these studies utilized beta2 -agonists at doses inapplicable to humans. Herein we show that a 4-week treatment period with daily therapeutic inhalation of beta2 -agonist increases insulin-stimulated whole-body glucose disposal in young healthy lean men. This effect was associated with an increase of lean mass but not with changes in GLUT4 and hexokinase II or basal glycogen content in skeletal muscle nor GLUT4 content in abdominal adipose tissue. These findings suggest that the enhanced insulin-stimulated whole-body glucose disposal induced by a period of beta2 -agonist treatment in humans, at least in part, is attributed to muscle hypertrophy. Our observations extend findings in rodents and highlight the therapeutic potential of beta2 -agonists to enhance the capacity for glucose disposal and whole-body insulin sensitivity, providing important knowledge with potential application in insulin resistance.

Project description:Synthetic beta-adrenergic agonists (BA) have broad biomedical and agricultural application for increasing lean body mass, yet a poor understanding of the biology underpinning these agents is limiting further drug discovery potential. Growing female pigs (77 ± 7 kg) were administered the BA, Ractopamine (20 ppm in feed), or the recombinant growth hormone (GH), Reporcin (10 mg/48 hrs injected) for 1, 3, 7, 13 (n = 10 per treatment, per time point) or 27 days (n = 15 per treatment). Using RNA-sequencing and inferred pathway analysis, we examined temporal changes to the Longissimus Dorsi skeletal muscle transcriptome (n = 3 per treatment, per time point) relative to a feed-only control cohort. Gene expression changes were affirmed by quantitative-PCR on all samples (n = 164). RNA-sequencing analysis revealed that BA treatment had greater effects than GH, and that asparagine synthetase (Asns) was the 5th most significantly increased gene by BA at day 3. ASNS protein expression was dramatically increased by BA treatment at day 7 (p < 0.05). The most significantly increased gene at day 3 was activating transcription factor 5 (Atf5), a transcription factor known to regulate ASNS gene expression. Gene and protein expression of Atf4, another known regulator of Asns expression, was not changed by BA treatment. Expression of more than 20 known Atf4 target genes were increased by BA treatment, suggesting that BA treatment induces an integrated stress response (ISR) in skeletal muscle of pigs. In support of this, mRNA expression of sestrin-2 (Sesn2) and cyclin-dependant kinase 1 alpha (Cdkn1a), two key stress-responsive genes and negative regulators of cellular growth, were also strongly increased from day 3 of BA treatment. Finally, tRNA charging was the most significantly enriched pathway induced by BA treatment, suggesting alterations to the translational capacity/efficiency of the muscle. BA-mediated changes to the skeletal muscle transcriptome are highly indicative of an integrated stress response (ISR), particularly genes relating to amino acid biosynthesis and protein translational capacity.

Dataset Information

Insulin/IGF1 signalling mediates the effects of ?₂ -adrenergic agonist on muscle proteostasis and growth.

Background

Methods

Results

Conclusions

Publications

Insulin/IGF1 signalling mediates the effects of β<sub>2</sub> -adrenergic agonist on muscle proteostasis and growth.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Insulin/IGF1 signalling mediates the effects of ?2 -adrenergic agonist on muscle proteostasis and growth.

Background

Methods

Results

Conclusions

Publications

Insulin/IGF1 signalling mediates the effects of β<sub>2</sub> -adrenergic agonist on muscle proteostasis and growth.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Insulin/IGF1 signalling mediates the effects of ?₂ -adrenergic agonist on muscle proteostasis and growth.