Mechanisms involved in follistatin‐induced hypertrophy and increased insulin action in skeletal muscle

Autor: Erik A. Richter, Zhencheng Li, Jonathan R. Davey, Kirstine N. Bojsen-Møller, Jonas R. Knudsen, Thomas E. Jensen, Carlos Henríquez-Olguín, Lykke Sylow, Lisbeth L. V. Møller, Estelle De Groote, Paul Gregorevic, Xiuqing Han, Sten Madsbad
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Male
0301 basic medicine
Follistatin
lcsh:Diseases of the musculoskeletal system
Glucose uptake
medicine.medical_treatment
Muscle wasting
Muscle hypertrophy
Mice
0302 clinical medicine
Parvovirinae
Glycaemic control
Faculty of Science
Orthopedics and Sports Medicine
Inhibin-beta Subunits
biology
TBC1D1
lcsh:Human anatomy
Dependovirus
Muscular Atrophy
medicine.anatomical_structure
030220 oncology & carcinogenesis
Original Article
Female
Signal Transduction
TGF-β
Adult
medicine.medical_specialty
Genetic Vectors
Gastric Bypass
lcsh:QM1-695
03 medical and health sciences
Insulin resistance
Physiology (medical)
Internal medicine
TGF beta signaling pathway
medicine
Animals
Humans
Obesity
Muscle
Skeletal
Protein kinase B
TGF‐β
business.industry
Insulin
Skeletal muscle
Original Articles
medicine.disease
Rats
HEK293 Cells
030104 developmental biology
Endocrinology
biology.protein
lcsh:RC925-935
business
Zdroj: Journal of Cachexia, Sarcopenia and Muscle, Vol 10, Iss 6, Pp 1241-1257 (2019)
Journal of Cachexia, Sarcopenia and Muscle
Han, X, Møller, L L V, De Groote, E, Bojsen-Møller, K N, Davey, J, Henríquez-Olguin, C, Li, Z, Knudsen, J R, Jensen, T E, Madsbad, S, Gregorevic, P, Richter, E A & Sylow, L 2019, ' Mechanisms involved in follistatin-induced hypertrophy and increased insulin action in skeletal muscle ', Journal of Cachexia, Sarcopenia and Muscle, vol. 10, no. 6, pp. 1241-1257 . https://doi.org/10.1002/jcsm.12474
ISSN: 2190-5991
2190-6009
DOI: 10.1002/jcsm.12474
Popis: BackgroundSkeletal muscle wasting is often associated with insulin resistance. A major regulator of muscle mass is the transforming growth factor β (TGF-β) superfamily, including activin A, which causes atrophy. TGF-β superfamily ligands also negatively regulate insulin-sensitive proteins, but whether this pathway contributes to insulin action remains to be determined.MethodsTo elucidate if TGF-β superfamily ligands regulate insulin action we used an adeno-associated virus gene editing approach to overexpress the activin A inhibitor, follistatin (Fst288) in mouse muscle of lean and diet-induced obese mice. We determined basal and insulin-stimulated 2 deoxy-glucose uptake using isotopic tracers in vivo. Furthermore, to evaluate whether circulating Fst and activin A concentrations are associated with obesity, insulin resistance, and weight loss in humans we analysed serum from morbidly obese subjects before, 1 week, and 1 year after Roux-en-Y gastric bypass (RYGB).ResultsFst288 muscle overexpression markedly increased in vivo insulin-stimulated (but not basal) glucose uptake (+75%, pConclusionsWe here present evidence that Fst is a potent regulator of insulin action in muscle and in addition to AKT and p70S6K, we identify TBC1D1, TBC1D4 and PAK1 as Fst targets. A possible role for Fst in regulating glycemic control is suggested because circulating Fst more than doubled post RYGB surgery, a treatment that markedly improved insulin sensitivity. These findings demonstrate the therapeutic potential of inhibiting TGF-β superfamily ligands to improve insulin action and Fst’s relevance to muscle wasting associated insulin resistant conditions in mice and humans.
Databáze: OpenAIRE
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