Pharmacologic Inhibition of Myostatin With a Myostatin Antibody Improves the Skeletal Muscle and Bone Phenotype of Male Insulin-Deficient Diabetic Mice.
Pharmacologic Inhibition of Myostatin With a Myostatin Antibody Improves the Skeletal Muscle and Bone Phenotype of Male Insulin-Deficient Diabetic Mice.
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1型糖尿病（T1D）与骨质和肌肉质量低、骨折风险增加和骨骼肌功能受损有关。肌生长抑制素（Myostatin）是一种在T1D患者体内全身性升高的肌肉生长因子，对肌肉质量和骨形成具有负调控作用。我们研究了在胰岛素缺乏、链脲佐菌素（STZ）诱导的糖尿病小鼠模型中，药理学抑制肌生长抑制素是否对骨骼和骨骼肌有保护作用。给DBA/2J雄性小鼠注射低剂量STZ（糖尿病）或对照（非糖尿病）。随后，植入胰岛素或棕榈酸酯Linbits，并给予肌肉生长抑制素（REGN647‐MyoAb）或对照（REGN1945‐ConAb）抗体8周。在体内评估体成分和收缩肌肉功能。定量测定全身肌肉生长抑制素、P1NP、CTX‐I和糖化血红蛋白（HbA1c），称重腓肠肌，分析肌纤维组成和选定基因的基因表达。分析皮质和骨小梁参数（股骨微计算机断层扫描评估），评估皮质骨强度（股骨骨干三点弯曲试验）。在糖尿病小鼠中，与单独使用MyoAb或胰岛素治疗相比，胰岛素/MyoAb联合治疗可显著提高瘦体重和腓肠肌重量。同样，与MyoAb或胰岛素治疗相比，胰岛素/MyoAb治疗的糖尿病小鼠骨骼肌中观察到更高的原始扭矩。此外，糖尿病患者的肌纤维横截面积（CSA）较低，胰岛素/MyoAb联合治疗可显著改善II型纤维的CSA。胰岛素、MyoAb或胰岛素/MyoAb治疗改善了小梁结构的几个参数（如骨体积分数[BV/TV]、小梁连通性密度[Conn.D]）和皮质结构（如皮质骨面积[Ct. d]）。[Ar.]，最小惯性矩[Imin])在糖尿病小鼠。最后，皮质骨生物力学性能（刚度和屈服力）也在胰岛素或MyoAb治疗下得到改善。综上所述，药物抑制肌肉生长抑制素对T1D小鼠模型的肌肉质量、肌肉功能和骨骼特性有益，其作用既独立于胰岛素的积极作用，又与胰岛素的积极作用相补充。©2023作者。JBMR Plus由Wiley期刊有限责任公司代表美国骨骼和矿物研究协会出版。本研究对胰岛素或肌生长抑制素抑制抗体治疗的雄性胰岛素缺乏糖尿病小鼠进行了研究，结果表明肌生长抑制素抑制对肌肉和骨骼有益，并且可以对胰岛素治疗产生附加效应。这些数据表明，肌生长抑制素是糖尿病骨病和糖尿病肌病的潜在靶点。
Type 1 diabetes (T1D) is associated with low bone and muscle mass, increased fracture risk, and impaired skeletal muscle function. Myostatin, a myokine that is systemically elevated in humans with T1D, negatively regulates muscle mass and bone formation. We investigated whether pharmacologic myostatin inhibition in a mouse model of insulin‐deficient, streptozotocin (STZ)‐induced diabetes is protective for bone and skeletal muscle. DBA/2J male mice were injected with low‐dose STZ (diabetic) or vehicle (non‐diabetic). Subsequently, insulin or palmitate Linbits were implanted and myostatin (REGN647‐MyoAb) or control (REGN1945‐ConAb) antibody was administered for 8 weeks. Body composition and contractile muscle function were assessed in vivo. Systemic myostatin, P1NP, CTX‐I, and glycated hemoglobin (HbA1c) were quantified, and gastrocnemii were weighed and analyzed for muscle fiber composition and gene expression of selected genes. Cortical and trabecular parameters were analyzed (micro‐computed tomography evaluations of femur) and cortical bone strength was assessed (three‐point bending test of femur diaphysis). In diabetic mice, the combination of insulin/MyoAb treatment resulted in significantly higher lean mass and gastrocnemius weight compared with MyoAb or insulin treatment alone. Similarly, higher raw torque was observed in skeletal muscle of insulin/MyoAb‐treated diabetic mice compared with MyoAb or insulin treatment. Additionally, muscle fiber cross‐sectional area (CSA) was lower with diabetes and the combination treatment with insulin/MyoAb significantly improved CSA in type II fibers. Insulin, MyoAb, or insulin/MyoAb treatment improved several parameters of trabecular architecture (eg, bone volume fraction [BV/TV], trabecular connectivity density [Conn.D]) and cortical structure (eg, cortical bone area [Ct. Ar.], minimum moment of inertia [Imin]) in diabetic mice. Lastly, cortical bone biomechanical properties (stiffness and yield force) were also improved with insulin or MyoAb treatment. In conclusion, pharmacologic myostatin inhibition is beneficial for muscle mass, muscle function, and bone properties in this mouse model of T1D and its effects are both independent and additive to the positive effects of insulin. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. This study on male insulin‐deficient diabetic mice treated with insulin or a myostatin inhibitory antibody demonstrates that myostatin inhibition is beneficial for muscle and bone and that it can have additive effects to insulin therapy. These data indicate that myostatin is a potential target for diabetic bone disease and diabetic myopathy.
遗传和药理学抑制肌抑制素在成骨的鼠模型模型中。
DOI：
10.1002/jbmr.4223
发表时间：
2021-04
期刊：
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
影响因子：
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作者：
Omosule CL;Gremminger VL;Aguillard AM;Jeong Y;Harrelson EN;Miloscio L;Mastaitis J;Rafique A;Kleiner S;Pfeiffer FM;Zhang A;Schulz LC;Phillips CL
通讯作者：
Phillips CL