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,...
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Wiley
2019-12-01
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Series: | Journal of Cachexia, Sarcopenia and Muscle |
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Online Access: | https://doi.org/10.1002/jcsm.12474 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Xiuqing Han Lisbeth Liliendal Valbjørn Møller Estelle De Groote Kirstine Nyvold Bojsen‐Møller Jonathan Davey Carlos Henríquez‐Olguin Zhencheng Li Jonas Roland Knudsen Thomas Elbenhardt Jensen Sten Madsbad Paul Gregorevic Erik Arne Richter Lykke Sylow |
spellingShingle |
Xiuqing Han Lisbeth Liliendal Valbjørn Møller Estelle De Groote Kirstine Nyvold Bojsen‐Møller Jonathan Davey Carlos Henríquez‐Olguin Zhencheng Li Jonas Roland Knudsen Thomas Elbenhardt Jensen Sten Madsbad Paul Gregorevic Erik Arne Richter Lykke Sylow Mechanisms involved in follistatin‐induced hypertrophy and increased insulin action in skeletal muscle Journal of Cachexia, Sarcopenia and Muscle Muscle wasting Follistatin TGF‐β Glucose uptake Insulin resistance Glycaemic control |
author_facet |
Xiuqing Han Lisbeth Liliendal Valbjørn Møller Estelle De Groote Kirstine Nyvold Bojsen‐Møller Jonathan Davey Carlos Henríquez‐Olguin Zhencheng Li Jonas Roland Knudsen Thomas Elbenhardt Jensen Sten Madsbad Paul Gregorevic Erik Arne Richter Lykke Sylow |
author_sort |
Xiuqing Han |
title |
Mechanisms involved in follistatin‐induced hypertrophy and increased insulin action in skeletal muscle |
title_short |
Mechanisms involved in follistatin‐induced hypertrophy and increased insulin action in skeletal muscle |
title_full |
Mechanisms involved in follistatin‐induced hypertrophy and increased insulin action in skeletal muscle |
title_fullStr |
Mechanisms involved in follistatin‐induced hypertrophy and increased insulin action in skeletal muscle |
title_full_unstemmed |
Mechanisms involved in follistatin‐induced hypertrophy and increased insulin action in skeletal muscle |
title_sort |
mechanisms involved in follistatin‐induced hypertrophy and increased insulin action in skeletal muscle |
publisher |
Wiley |
series |
Journal of Cachexia, Sarcopenia and Muscle |
issn |
2190-5991 2190-6009 |
publishDate |
2019-12-01 |
description |
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. |
topic |
Muscle wasting Follistatin TGF‐β Glucose uptake Insulin resistance Glycaemic control |
url |
https://doi.org/10.1002/jcsm.12474 |
work_keys_str_mv |
AT xiuqinghan mechanismsinvolvedinfollistatininducedhypertrophyandincreasedinsulinactioninskeletalmuscle AT lisbethliliendalvalbjørnmøller mechanismsinvolvedinfollistatininducedhypertrophyandincreasedinsulinactioninskeletalmuscle AT estelledegroote mechanismsinvolvedinfollistatininducedhypertrophyandincreasedinsulinactioninskeletalmuscle AT kirstinenyvoldbojsenmøller mechanismsinvolvedinfollistatininducedhypertrophyandincreasedinsulinactioninskeletalmuscle AT jonathandavey mechanismsinvolvedinfollistatininducedhypertrophyandincreasedinsulinactioninskeletalmuscle AT carloshenriquezolguin mechanismsinvolvedinfollistatininducedhypertrophyandincreasedinsulinactioninskeletalmuscle AT zhenchengli mechanismsinvolvedinfollistatininducedhypertrophyandincreasedinsulinactioninskeletalmuscle AT jonasrolandknudsen mechanismsinvolvedinfollistatininducedhypertrophyandincreasedinsulinactioninskeletalmuscle AT thomaselbenhardtjensen mechanismsinvolvedinfollistatininducedhypertrophyandincreasedinsulinactioninskeletalmuscle AT stenmadsbad mechanismsinvolvedinfollistatininducedhypertrophyandincreasedinsulinactioninskeletalmuscle AT paulgregorevic mechanismsinvolvedinfollistatininducedhypertrophyandincreasedinsulinactioninskeletalmuscle AT erikarnerichter mechanismsinvolvedinfollistatininducedhypertrophyandincreasedinsulinactioninskeletalmuscle AT lykkesylow mechanismsinvolvedinfollistatininducedhypertrophyandincreasedinsulinactioninskeletalmuscle |
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1724847831714365440 |
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doaj-dd8c8c9c3b104cf7b0bbb947b4cf74692020-11-25T02:26:19ZengWileyJournal of Cachexia, Sarcopenia and Muscle2190-59912190-60092019-12-011061241125710.1002/jcsm.12474Mechanisms involved in follistatin‐induced hypertrophy and increased insulin action in skeletal muscleXiuqing Han0Lisbeth Liliendal Valbjørn Møller1Estelle De Groote2Kirstine Nyvold Bojsen‐Møller3Jonathan Davey4Carlos Henríquez‐Olguin5Zhencheng Li6Jonas Roland Knudsen7Thomas Elbenhardt Jensen8Sten Madsbad9Paul Gregorevic10Erik Arne Richter11Lykke Sylow12Section of Molecular Physiology, Department of Nutrition, Exercise, and Sports, Faculty of Science University of Copenhagen Copenhagen DenmarkSection of Molecular Physiology, Department of Nutrition, Exercise, and Sports, Faculty of Science University of Copenhagen Copenhagen DenmarkFaculty of Motor Science, Institute of Neuroscience Université Catholique de Louvain Ottignies‐Louvain‐la‐Neuve BelgiumDepartment of Endocrinology Copenhagen University Hospital Hvidovre Hvidovre DenmarkCenter for Muscle Research, Department of Physiology University of Melbourne Melbourne AustraliaSection of Molecular Physiology, Department of Nutrition, Exercise, and Sports, Faculty of Science University of Copenhagen Copenhagen DenmarkSection of Molecular Physiology, Department of Nutrition, Exercise, and Sports, Faculty of Science University of Copenhagen Copenhagen DenmarkSection of Molecular Physiology, Department of Nutrition, Exercise, and Sports, Faculty of Science University of Copenhagen Copenhagen DenmarkSection of Molecular Physiology, Department of Nutrition, Exercise, and Sports, Faculty of Science University of Copenhagen Copenhagen DenmarkDepartment of Endocrinology Copenhagen University Hospital Hvidovre Hvidovre DenmarkCenter for Muscle Research, Department of Physiology University of Melbourne Melbourne AustraliaSection of Molecular Physiology, Department of Nutrition, Exercise, and Sports, Faculty of Science University of Copenhagen Copenhagen DenmarkSection of Molecular Physiology, Department of Nutrition, Exercise, and Sports, Faculty of Science University of Copenhagen Copenhagen DenmarkAbstract 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.https://doi.org/10.1002/jcsm.12474Muscle wastingFollistatinTGF‐βGlucose uptakeInsulin resistanceGlycaemic control |