Bunn R Clay, Adatorwovor Reuben, Ray Philip D, Keeble Alexander R, Fry Christopher S, Uppuganti Sasidhar, Nyman Jeffry S, Fowlkes John L, Kalaitzoglou Evangelia
Department of Pediatrics and Barnstable Brown Diabetes Center, University of Kentucky, Lexington, KY, United States.
Department of Biostatistics, College of Public Health, University of Kentucky, Lexington, KY, United States.
Front Endocrinol (Lausanne). 2025 Jun 12;16:1558740. doi: 10.3389/fendo.2025.1558740. eCollection 2025.
Type 1 diabetes is associated with deficits in both skeletal muscle and bone. Inhibition of myostatin, a negative regulator of muscle mass, was explored as a druggable target to improve the musculoskeletal phenotype associated with insulin-deficient diabetes in female mice.
We investigated whether administration of an inhibitory myostatin antibody (MyoAb) in streptozotocin-induced diabetes in female mice is protective for skeletal muscle and bone. DBA/2J female mice were injected with low-dose streptozotocin or with citrate buffer (vehicle). Subsequently, mice were implanted with insulin-containing or vehicle pellets, with groups being randomized to myostatin or control antibody for 8 weeks. At study end, body composition and contractile muscle function were assessed, systemic myostatin and glycated hemoglobin were quantified, gastrocnemii were weighed and analyzed for fiber type composition, and femur microarchitecture and biomechanical properties were analyzed.
Glycated hemoglobin was significantly higher in diabetic mice compared to non-diabetic mice and diabetic mice treated with insulin. In diabetic mice, the combination of insulin and MyoAb resulted in higher lean mass, higher average gastrocnemius weight and larger muscle fiber size (Type IIB, IIX and hybrid fibers) compared to no treatment. contractile muscle function testing showed that insulin increased muscle torque in diabetic mice, however there was no effect of the MyoAb. Lastly, microarchitecture analysis of the distal femur showed improvement in some, but not all trabecular bone properties, in mice treated with insulin alone or together with MyoAb. Specifically, trabecular thickness and trabecular bone volume fraction were higher with combination treatment compared to insulin treatment alone.
Myostatin inhibition when used in conjunction with insulin treatment improves muscle mass and trabecular bone properties in a mouse model of insulin-deficient diabetes in female mice.
1型糖尿病与骨骼肌和骨骼缺陷有关。肌肉生长抑制素是肌肉质量的负调节因子，人们探索将其抑制作为一个可药物作用的靶点，以改善雌性小鼠中与胰岛素缺乏型糖尿病相关的肌肉骨骼表型。
我们研究了在链脲佐菌素诱导的雌性糖尿病小鼠中给予抑制性肌肉生长抑制素抗体（MyoAb）是否对骨骼肌和骨骼具有保护作用。将DBA/2J雌性小鼠注射低剂量链脲佐菌素或柠檬酸盐缓冲液（赋形剂）。随后，给小鼠植入含胰岛素或赋形剂的微渗透泵，将各组随机分为接受肌肉生长抑制素抗体或对照抗体治疗8周。在研究结束时，评估身体组成和收缩肌肉功能，定量全身肌肉生长抑制素和糖化血红蛋白，称量腓肠肌并分析其纤维类型组成，分析股骨的微观结构和生物力学特性。
与非糖尿病小鼠和接受胰岛素治疗的糖尿病小鼠相比，糖尿病小鼠的糖化血红蛋白显著更高。在糖尿病小鼠中，与未治疗相比，胰岛素和MyoAb联合使用导致更高的瘦体重、更高的平均腓肠肌重量和更大的肌纤维尺寸（IIB型、IIX型和混合型纤维）。收缩肌肉功能测试表明，胰岛素增加了糖尿病小鼠的肌肉扭矩，然而MyoAb没有效果。最后，对股骨远端的微观结构分析表明，单独使用胰岛素或与MyoAb联合治疗后，小鼠的一些（但不是全部）小梁骨特性有所改善。具体而言，联合治疗组的小梁厚度和小梁骨体积分数高于单独胰岛素治疗组。
在雌性小鼠胰岛素缺乏型糖尿病模型中，肌肉生长抑制素抑制与胰岛素治疗联合使用可改善肌肉质量和小梁骨特性。
