ESPE Abstracts

Background: Type 1 diabetes is associated with deficits in skeletal muscle and bone mass and quality. Inhibition of myostatin, a negative regulator of muscle mass, was explored as a therapeutic modality to improve the muscle and bone phenotype associated with insulin-deficient diabetes.

Methods: We investigated whether an inhibitory myostatin antibody in streptozotocin (STZ)-induced diabetes in female mice is protective for skeletal muscle and bone. DBA/2J female mice (n = 6-10/group) were injected with low-dose STZ (diabetic-D) or vehicle (non-diabetic-ND). After diabetes confirmation, insulin (Ins) or vehicle (Veh) LinBits were implanted and myostatin (REGN647-MyoAb) antibody or control (REGN1945-ConAb) antibody (10 mg/kg) was injected subcutaneously twice/week. Prior to euthanasia (8 weeks of treatment), body composition (EchoMRI) and in vivo contractile muscle function were assessed. Systemic myostatin and glycated hemoglobin (HbA1c) were quantified, gastrocnemii were harvested and weighed, and femur microarchitecture was analyzed (microCT).

Results: HbA1c was significantly higher in D mice not treated with insulin compared to ND mice and D mice treated with insulin. Systemic myostatin was lower in D-Veh-ConAb (16.3 ng/ml) compared to ND-Veh-ConAb (31.8 ng/ml, P <0.001) or D-Ins-ConAb mice (15.9 ng/ml, P <0.001). In diabetic mice, the combination of insulin/ MyoAb resulted in higher lean mass compared to MyoAb or insulin alone (D-Ins-MyoAb vs D-Veh-MyoAb, 19.1 g vs 16.1 g, P <0.001 and D-Ins-MyoAb vs D-Ins-ConAb, 19.1 g vs 17.3 g, P = 0.03) and higher average gastrocnemius weight (D-Ins-MyoAb vs D-Veh-MyoAb, 0.1 g vs 0.06 g, P <0.001 and D-Ins-MyoAb vs D-Ins-ConAb, 0.1 g vs 0.09 g, P = 0.056). in vivo contractile muscle function testing showed that insulin increased raw muscle torque in D mice, however there was no effect of MyoAb. Lastly, microCT analysis of the femur showed improvement in some, but not all trabecular bone properties, in mice treated with insulin alone or together with MyoAb. Specifically, trabecular thickness was improved with combination treatment of insulin/MyoAb compared to insulin treatment alone (D-Ins-MyoAb vs D-Ins-ConAb, 0.04 mm vs 0.03 mm, P = 0.009), as was trabecular bone volume fraction (D-Ins-MyoAb vs D-Ins-ConAb, 5.87% vs 4.61%, P = 0.03).

Conclusion: Myostatin inhibition with a myostatin inhibitory antibody 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.