Mechanisms involved in follistatin-induced hypertrophy and increased insulin action in skeletal muscle.
Mechanisms involved in follistatin-induced hypertrophy and increased insulin action in skeletal muscle.
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DOI：
10.1002/jcsm.12474
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发表时间：
2019-12
期刊：
影响因子：
--
通讯作者：
Sylow L
中科院分区：
文献类型：
--
作者：
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
骨骼肌萎缩通常与胰岛素抵抗有关。肌肉质量的主要调节因子是转化生长因子β（TGF-β）超家族，包括导致萎缩的激活素A。TGF-β超家族配体也负调节胰岛素敏感蛋白，但该途径是否有助于胰岛素作用仍有待确定。为了阐明TGF-β超家族配体是否调节胰岛素作用，我们使用腺相关病毒基因编辑方法在瘦和饮食诱导的肥胖小鼠的小鼠肌肉中过表达激活素A抑制剂卵泡抑素（Fst 288）。我们在体内使用同位素示踪剂测定了基础和胰岛素刺激的2-脱氧葡萄糖摄取。此外，为了评估循环Fst和激活素A浓度是否与人类肥胖、胰岛素抵抗和体重减轻相关，我们分析了Roux-en-Y胃旁路术（RYGB）前、1周和1年后病态肥胖受试者的血清。Fst 288肌肉过表达显著增加体内胰岛素刺激的（但不是基础的）葡萄糖摄取（+75%，P < 0.05），并增加AKT、TBC 1D 4、PAK 1、丙酮酸脱氢酶-E1α和p70 S6 K的蛋白表达和细胞内胰岛素信号传导，同时降低TBC 1D 1信号传导（P < 0.05）。Fst 288增加了基础和胰岛素刺激的蛋白质合成，但在Fst 288驱动的肥大和胰岛素刺激的葡萄糖摄取增加之间未观察到相关性。重要的是，Fst 288在胰岛素抵抗饮食诱导的肥胖小鼠中完全正常化肌肉葡萄糖摄取。RYGB手术使循环Fst增加一倍，并降低了病态肥胖血糖正常患者手术后1周的激活素A浓度（-24%，P < 0.05），而1年后的重大体重减轻并没有进一步改变浓度。我们在这里提出的证据表明，Fst是肌肉中胰岛素作用的有效调节剂，除了AKT和p70 S6 K之外，我们还确定了TBC 1D 1，TBC 1D 4，丙酮酸脱氢酶-E1α和PAK 1作为Fst靶点。RYGB手术后，循环Fst增加了一倍以上，这种治疗显著改善了胰岛素敏感性，表明Fst在调节血糖控制中的作用。这些发现证明了抑制TGF-β超家族配体改善胰岛素作用的治疗潜力以及Fst与小鼠和人类肌肉萎缩相关胰岛素抵抗状况的相关性。
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. 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). 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. 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.
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影响因子：
15.9
作者：
Cusi, K;Maezono, K;Mandarino, LJ
通讯作者：
Mandarino, LJ
DOI：
10.1016/j.bbrc.2013.10.005
发表时间：
2013-11-08
影响因子：
3.1
作者：
Ikeda, Shin-ichi;Tamura, Yoshifumi;Watada, Hirotaka
通讯作者：
Watada, Hirotaka
影响因子：
7.7
作者：
JeBailey, Lellean;Wanono, Oshrit;Klip, Amira
通讯作者：
Klip, Amira
影响因子：
4.1
作者：
FERRE, P;LETURQUE, A;GIRARD, J
通讯作者：
GIRARD, J
影响因子：
8
作者：
Davey, Jonathan R.;Watt, Kevin I.;Gregorevic, Paul
通讯作者：
Gregorevic, Paul