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Using AAV vectors expressing the ?2-adrenoceptor or associated G? proteins to modulate skeletal muscle mass and muscle fibre size.

ABSTRACT: Anabolic ?2-adrenoceptor (?2-AR) agonists have been proposed as therapeutics for treating muscle wasting but concerns regarding possible off-target effects have hampered their use. We investigated whether ?2-AR-mediated signalling could be modulated in skeletal muscle via gene delivery to the target tissue, thereby avoiding the risks of ?2-AR agonists. In mice, intramuscular administration of a recombinant adeno-associated virus-based vector (rAAV vector) expressing the ?2-AR increased muscle mass by >20% within 4 weeks. This hypertrophic response was comparable to that of 4 weeks' treatment with the ?2-AR agonist formoterol, and was not ablated by mTOR inhibition. Increasing expression of inhibitory (G?i2) and stimulatory (G?sL) G-protein subunits produced minor atrophic and hypertrophic changes in muscle mass, respectively. Furthermore, G?i2 over-expression prevented AAV:?2-AR mediated hypertrophy. Introduction of the non-muscle G?s isoform, G?sXL elicited hypertrophy comparable to that achieved by AAV:?2-AR. Moreover, G?sXL gene delivery was found to be capable of inducing hypertrophy in the muscles of mice lacking functional ?1- and ?2-ARs. These findings demonstrate that gene therapy-based interventions targeting the ?2-AR pathway can promote skeletal muscle hypertrophy independent of ligand administration, and highlight novel methods for potentially modulating muscle mass in settings of disease.

SUBMITTER: Hagg A

PROVIDER: S-EPMC4789796 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Using AAV vectors expressing the β2-adrenoceptor or associated Gα proteins to modulate skeletal muscle mass and muscle fibre size.

Hagg Adam A Colgan Timothy D TD Thomson Rachel E RE Qian Hongwei H Lynch Gordon S GS Gregorevic Paul P

Scientific reports 20160314

Anabolic β2-adrenoceptor (β2-AR) agonists have been proposed as therapeutics for treating muscle wasting but concerns regarding possible off-target effects have hampered their use. We investigated whether β2-AR-mediated signalling could be modulated in skeletal muscle via gene delivery to the target tissue, thereby avoiding the risks of β2-AR agonists. In mice, intramuscular administration of a recombinant adeno-associated virus-based vector (rAAV vector) expressing the β2-AR increased muscle ma ...[more]

PMID: 26972746

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Project description:BackgroundSkeletal muscle mass begins to decline from 40 years of age. Limited data suggest that dietary fibre may modify lean body mass (BM), of which skeletal muscle is the largest and most malleable component. We investigated the relationship between dietary fibre intake, skeletal muscle mass and associated metabolic and functional parameters in adults aged 40 years and older.MethodsWe analysed cross-sectional data from the US National Health and Nutrition Examination Survey between 2011 and 2018 from adults aged 40 years and older. Covariate-adjusted multiple linear regression analyses were used to evaluate the association between dietary fibre intake and BM components (BM, body mass index [BMI], total lean mass, appendicular lean mass, bone mineral content, total fat, trunk fat; n = 6454), glucose homeostasis (fasting glucose, fasting insulin, HOMA2-IR; n = 5032) and skeletal muscle strength (combined grip strength; n = 5326). BM components and skeletal muscle strength were expressed relative to BM (per kg of BM).ResultsHigher intakes of dietary fibre were significantly associated with increased relative total lean mass (β: 0.69 g/kg BM; 95% CI, 0.48-0.89 g/kg BM; P < 0.001), relative appendicular lean mass (β: 0.34 g/kg BM; 95% CI, 0.23-0.45 g/kg BM; P < 0.001), relative bone mineral content (β: 0.05 g/kg BM; 95% CI, 0.02-0.07 g/kg BM; P < 0.001) and relative combined grip strength (β: 0.002 kg/kg BM; 95% CI, 0.001-0.003 kg/kg BM; P < 0.001). Conversely, higher dietary fibre intakes were significantly associated with a lower BM (β: -0.20; 95% CI, -0.28 to -0.11 kg; P < 0.001), BMI (β: -0.08 kg/m2 ; 95%CI, -0.10 to -0.05 kg/m2 ), relative total fat (β: -0.68 g/kg BM; 95% CI, -0.89 to -0.47 g/kg BM; P < 0.001), relative trunk fat (β: -0.48 g/kg BM; 95%CI, -0.63 to -0.33 g/kg; P < 0.001), fasting glucose (β: -0.01 mmol/L; 95% CI, -0.02 to -0.00 mmol/L; P = 0.017), fasting insulin (β: -0.71 pmol/L; 95% CI, -1.01 to -0.41 pmol/L; P < 0.001) and HOMA2-IR (β: -0.02 AU; 95% CI, -0.02 to -0.01 AU; P < 0.001).ConclusionsHigher dietary fibre intakes are associated with a lower BM and enhanced body composition, characterized by a reduction in fat mass and an increase in lean mass. Higher dietary fibre intakes were also associated with improvements in glucose homeostasis and skeletal muscle strength. Increasing dietary fibre intake may be a viable strategy to prevent age-associated declines in skeletal muscle mass.

Dataset Information

Using AAV vectors expressing the ?2-adrenoceptor or associated G? proteins to modulate skeletal muscle mass and muscle fibre size.

Publications

Using AAV vectors expressing the β2-adrenoceptor or associated Gα proteins to modulate skeletal muscle mass and muscle fibre size.

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