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

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Standard

Mechanisms involved in follistatin-induced hypertrophy and increased insulin action in skeletal muscle. / Han, Xiuqing; Møller, Lisbeth Liliendal Valbjørn; De Groote, Estelle; Bojsen-Møller, Kirstine Nyvold; Davey, Jonathan; Henríquez-Olguin, Carlos; Li, Zhencheng; Knudsen, Jonas Roland; Jensen, Thomas Elbenhardt; Madsbad, Sten; Gregorevic, Paul; Richter, Erik A; Sylow, Lykke.

I: Journal of Cachexia, Sarcopenia and Muscle, Bind 10, Nr. 6, 2019, s. 1241-1257.

Publikation: Bidrag til tidsskriftTidsskriftartikel

Harvard

Han, X, Møller, LLV, De Groote, E, Bojsen-Møller, KN, Davey, J, Henríquez-Olguin, C, Li, Z, Knudsen, JR, Jensen, TE, Madsbad, S, Gregorevic, P, Richter, EA & Sylow, L 2019, 'Mechanisms involved in follistatin-induced hypertrophy and increased insulin action in skeletal muscle', Journal of Cachexia, Sarcopenia and Muscle, bind 10, nr. 6, s. 1241-1257. https://doi.org/10.1002/jcsm.12474

APA

Han, X., Møller, L. L. V., De Groote, E., Bojsen-Møller, K. N., Davey, J., Henríquez-Olguin, C., ... Sylow, L. (2019). Mechanisms involved in follistatin-induced hypertrophy and increased insulin action in skeletal muscle. Journal of Cachexia, Sarcopenia and Muscle, 10(6), 1241-1257. https://doi.org/10.1002/jcsm.12474

Vancouver

Han X, Møller LLV, De Groote E, Bojsen-Møller KN, Davey J, Henríquez-Olguin C o.a. Mechanisms involved in follistatin-induced hypertrophy and increased insulin action in skeletal muscle. Journal of Cachexia, Sarcopenia and Muscle. 2019;10(6):1241-1257. https://doi.org/10.1002/jcsm.12474

Author

Han, Xiuqing ; Møller, Lisbeth Liliendal Valbjørn ; De Groote, Estelle ; Bojsen-Møller, Kirstine Nyvold ; Davey, Jonathan ; Henríquez-Olguin, Carlos ; Li, Zhencheng ; Knudsen, Jonas Roland ; Jensen, Thomas Elbenhardt ; Madsbad, Sten ; Gregorevic, Paul ; Richter, Erik A ; Sylow, Lykke. / Mechanisms involved in follistatin-induced hypertrophy and increased insulin action in skeletal muscle. I: Journal of Cachexia, Sarcopenia and Muscle. 2019 ; Bind 10, Nr. 6. s. 1241-1257.

Bibtex

@article{c19a9bd299d5421ba4449165ddea1b0a,
title = "Mechanisms involved in follistatin-induced hypertrophy and increased insulin action in skeletal muscle",
abstract = "Background: Skeletal 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.Methods: To elucidate if TGF-β superfamily ligands regulate insulin action, we used an adeno-associated virus gene editing approach to overexpress an 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).Results: Fst288 muscle overexpression markedly increased in vivo insulin-stimulated (but not basal) glucose uptake (+75{\%}, P < 0.05) and increased protein expression and intracellular insulin signalling of AKT, TBC1D4, PAK1, pyruvate dehydrogenase-E1α, and p70S6K, while decreasing TBC1D1 signaling (P < 0.05). Fst288 increased both basal and insulin-stimulated protein synthesis, but no correlation was observed between the Fst288-driven hypertrophy and the increase in insulin-stimulated glucose uptake. Importantly, Fst288 completely normalized muscle glucose uptake in insulin-resistant diet-induced obese mice. RYGB surgery doubled circulating Fst and reduced activin A (-24{\%}, P < 0.05) concentration 1 week after surgery before any significant weight loss in morbidly obese normoglycemic patients, while major weight loss after 1 year did not further change the concentrations.Conclusions: We 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, pyruvate dehydrogenase-E1α, and PAK1 as Fst targets. Circulating Fst more than doubled post-RYGB surgery, a treatment that markedly improved insulin sensitivity, suggesting a role for Fst in regulating glycaemic control. 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.",
keywords = "Faculty of Science, Muscle wasting, Follistatin, TGF-β, Glucose uptake, Insulin resistance, Glycaemic control",
author = "Xiuqing Han and M{\o}ller, {Lisbeth Liliendal Valbj{\o}rn} and {De Groote}, Estelle and Bojsen-M{\o}ller, {Kirstine Nyvold} and Jonathan Davey and Carlos Henr{\'i}quez-Olguin and Zhencheng Li and Knudsen, {Jonas Roland} and Jensen, {Thomas Elbenhardt} and Sten Madsbad and Paul Gregorevic and Richter, {Erik A} and Lykke Sylow",
note = "{\circledC} 2019 The Authors Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.",
year = "2019",
doi = "10.1002/jcsm.12474",
language = "English",
volume = "10",
pages = "1241--1257",
journal = "Journal of Cachexia, Sarcopenia and Muscle",
issn = "2190-5991",
publisher = "Wiley - V C H Verlag GmbH & Co. KGaA",
number = "6",

}

RIS

TY - JOUR

T1 - Mechanisms involved in follistatin-induced hypertrophy and increased insulin action in skeletal muscle

AU - Han, Xiuqing

AU - Møller, Lisbeth Liliendal Valbjørn

AU - De Groote, Estelle

AU - Bojsen-Møller, Kirstine Nyvold

AU - Davey, Jonathan

AU - Henríquez-Olguin, Carlos

AU - Li, Zhencheng

AU - Knudsen, Jonas Roland

AU - Jensen, Thomas Elbenhardt

AU - Madsbad, Sten

AU - Gregorevic, Paul

AU - Richter, Erik A

AU - Sylow, Lykke

N1 - © 2019 The Authors Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.

PY - 2019

Y1 - 2019

N2 - Background: Skeletal 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.Methods: To elucidate if TGF-β superfamily ligands regulate insulin action, we used an adeno-associated virus gene editing approach to overexpress an 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).Results: Fst288 muscle overexpression markedly increased in vivo insulin-stimulated (but not basal) glucose uptake (+75%, P < 0.05) and increased protein expression and intracellular insulin signalling of AKT, TBC1D4, PAK1, pyruvate dehydrogenase-E1α, and p70S6K, while decreasing TBC1D1 signaling (P < 0.05). Fst288 increased both basal and insulin-stimulated protein synthesis, but no correlation was observed between the Fst288-driven hypertrophy and the increase in insulin-stimulated glucose uptake. Importantly, Fst288 completely normalized muscle glucose uptake in insulin-resistant diet-induced obese mice. RYGB surgery doubled circulating Fst and reduced activin A (-24%, P < 0.05) concentration 1 week after surgery before any significant weight loss in morbidly obese normoglycemic patients, while major weight loss after 1 year did not further change the concentrations.Conclusions: We 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, pyruvate dehydrogenase-E1α, and PAK1 as Fst targets. Circulating Fst more than doubled post-RYGB surgery, a treatment that markedly improved insulin sensitivity, suggesting a role for Fst in regulating glycaemic control. 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.

AB - Background: Skeletal 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.Methods: To elucidate if TGF-β superfamily ligands regulate insulin action, we used an adeno-associated virus gene editing approach to overexpress an 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).Results: Fst288 muscle overexpression markedly increased in vivo insulin-stimulated (but not basal) glucose uptake (+75%, P < 0.05) and increased protein expression and intracellular insulin signalling of AKT, TBC1D4, PAK1, pyruvate dehydrogenase-E1α, and p70S6K, while decreasing TBC1D1 signaling (P < 0.05). Fst288 increased both basal and insulin-stimulated protein synthesis, but no correlation was observed between the Fst288-driven hypertrophy and the increase in insulin-stimulated glucose uptake. Importantly, Fst288 completely normalized muscle glucose uptake in insulin-resistant diet-induced obese mice. RYGB surgery doubled circulating Fst and reduced activin A (-24%, P < 0.05) concentration 1 week after surgery before any significant weight loss in morbidly obese normoglycemic patients, while major weight loss after 1 year did not further change the concentrations.Conclusions: We 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, pyruvate dehydrogenase-E1α, and PAK1 as Fst targets. Circulating Fst more than doubled post-RYGB surgery, a treatment that markedly improved insulin sensitivity, suggesting a role for Fst in regulating glycaemic control. 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.

KW - Faculty of Science

KW - Muscle wasting

KW - Follistatin

KW - TGF-β

KW - Glucose uptake

KW - Insulin resistance

KW - Glycaemic control

U2 - 10.1002/jcsm.12474

DO - 10.1002/jcsm.12474

M3 - Journal article

C2 - 31402604

VL - 10

SP - 1241

EP - 1257

JO - Journal of Cachexia, Sarcopenia and Muscle

JF - Journal of Cachexia, Sarcopenia and Muscle

SN - 2190-5991

IS - 6

ER -

ID: 225957333