IMPE Abstracts

Type 1 diabetes (T1D) is associated with low bone and muscle mass, increased fracture risk and impaired skeletal muscle function. Myostatin (GDF8), a myokine that is systemically elevated in humans with T1D, negatively regulates muscle mass and bone formation. We investigated whether an inhibitory myostatin antibody in streptozotocin (STZ)-induced diabetes mouse model is protective for bone and skeletal muscle. DBA/2J male mice (n=9 -10/group) were injected with low-dose STZ (diabetic-D) or vehicle (non-diabetic-ND). After diabetes confirmation, insulin (Ins) or palmitate (Palm) LinBits were implanted and myostatin (REGN647-MyoAb) or control (REGN1945-ConAb) antibody was injected (10 mg/kg) once-twice/week. Prior to euthanasia (8 weeks), 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 properties were analyzed (microCT). Diabetic mice had lower whole body, lean and fat mass after diabetes induction (baseline). HbA1c was significantly higher in D compared to ND mice. Systemic myostatin adjusted for lean mass was lower in D-Palm-ConAb (1572 pg/ml/g lean mass) compared to ND-Palm-ConAb (1937 pg/ml/g, P=0.026) or D-Ins-ConAb mice (1945 pg/ml/g, P=0.027). In diabetic mice, MyoAb resulted in higher lean mass (D-Palm-MyoAb vs D-Palm-ConAb, 20.3 g vs 17.7 g, P= 0.014) and higher average gastrocnemius weight compared to control antibody treatment (D-Palm-MyoAb vs D-Palm-ConAb, 0.078 g vs 0.066 g, P=0.045). Similarly, insulin treatment resulted in higher lean mass and average gastrocnemius weight (D-Ins-ConAb vs D-Palm-ConAb, lean mass: 20.7 g vs 17.7 g, P<0.001, gastrocnemius weight: 0.089 g vs 0.066 g, P<0.001). The combination of insulin/ MyoAb resulted in higher lean mass and average gastrocnemius weight, compared to MyoAb or insulin alone. Fat mass was similar between diabetic mice, irrespective of insulin or antibody treatment. In vivo contractile muscle function showed that insulin (P=0.019) and MyoAb (P=0.035) increased raw muscle torque in D mice. Lastly, microCT analysis of the femur showed improvement in trabecular properties in mice treated with insulin alone or together with MyoAb. Specifically, Bone Volume Fraction (BV/TV) was higher in D-Ins-MyoAb compared to D-Ins-ConAb mice (0.076 vs 0.0597, P= 0.003) and Trabecular Connectivity (Conn Dens) was also higher (255.6 mm-3 vs 182.5 mm-3, P=0.001). Myostatin inhibition with REGN647 improves muscle mass, muscle function and trabecular bone properties in a mouse model of T1D and its effects are mostly independent and additive to the positive effects of insulin.