GDF8 and activin A blockade protects against GLP-1-induced muscle loss while enhancing fat loss in obese male mice and non-human primates

Abstract

Glucagon-like peptide-1 receptor agonists act via appetite suppression and caloric restriction. These treatments can result in significant muscle loss, likely due to evolutionary mechanisms protecting against food scarcity as muscle is a major energy utilizer. One mechanism that reduces muscle mass involves activation of type II activin receptors, ActRIIA/B, which yield profound muscle growth in humans when blocked. We previously demonstrated GDF8, also known as myostatin, and activin A are the two major ActRIIA/B ligands mediating muscle minimization. Here, we report that dual blockade can also prevent muscle loss associated with glucagon-like peptide-1 receptor agonists - and even increase muscle mass - in both obese mice and non-human primates; moreover, this muscle preservation enhances fat loss and is metabolically beneficial. These data raise the possibility that supplementing glucagon-like peptide-1 receptor agonist treatment with GDF8 and activin A blockade could greatly improve the quality of weight loss during the treatment of obesity in humans.

Fig. 1. Myostatin and activin A blockade induce additive fat mass loss with semaglutide in DIO mice.

Male diet-induced, obese C57Bl/6 mice were treated for four weeks with control antibody (white circles, n = 7), Sema (blue squares, n = 8), α-MSTN/ (orange triangles, n = 7) or Sema + α-MSTN/α-ActA (purple diamonds, n = 8). a Body weight, b lean mass, and c fat mass in percent change from baseline as measured by EchoMRI. d, e Terminal liver fat area and triglyceride content. f Representative H&E images from each group. Data are presented as mean ± SEM. a–c * P < 0.05 vs. vehicle, # P < 0.05 vs. Sema, ^ P < 0.05 vs. α-MSTN/α-ActA by two-way RM ANOVA. d * P < 0.05 vs. vehicle, # P < 0.01 vs. Sema, ^ P < 0.01 vs. α-MSTN/α-ActA by one-way ANOVA. e * P < 0.05, ** P < 0.01, **** P < 0.0001 vs. vehicle by one-way ANOVA. α-MSTN: anti-myostatin antibody, α-ActA: anti-activin a antibody, sema: semaglutide.

Fig. 2. Myostatin and activin A blockade induce additive fat mass loss with GLP-1R agonism in obese non-human primates.

Male, obese cynomolgus monkeys were treated for 20 weeks with control antibody (white circles, n = 10), Sema (blue squares, n = 9), α-MSTN/α-ActA (orange triangles, n = 8) or Sema + α-MSTN/α-ActA (purple diamonds, n = 10). a Body weight, expressed as percent change from baseline. b Daily total energy intake (TEI) expressed as a seven-day average in kilocalories (kcal) for each group. Each time point represents the daily average of the previous seven days ± SEM. c–e Total mass, fat mass, and lean mass measured by DXA scanning and expressed as percent change from baseline. Data are presented as mean ± SEM. Panels a-e: * P < 0.05 vs. vehicle, # P < 0.05 vs. Sema, ^ P < 0.05 vs. α-MSTN + α-ActA, $ P < 0.05 vs. Sema + α-MSTN + α-ActA, + P < 0.05 vs. baseline for the last timepoint of each group. Stats by two-way repeated measures ANOVA. α-MSTN: anti-myostatin antibody, α-ActA: anti-activin a antibody, sema: semaglutide, DXA dual energy x-ray absorptiometry.

Fig. 3. Addition of Myostatin and activin A blockade to semaglutide further improves glucose, HbA1c%, LDL-C and HDL-C.

Male, obese cynomolgus monkeys were treated for 20 weeks with control antibody (white circles, n = 10), Sema (blue squares, n = 9), α-MSTN/α-ActA (orange triangles, n = 8), or Sema + α-MSTN/α-ActA (purple diamonds, n = 10). Clinical chemistry results for a fasting glucose b hemoglobin A1c (HbA1c%), c low-density lipoprotein (LDL-C), and d high-density lipoprotein (HDL-C). Blood for all values was taken in the morning before breakfast. All data points are mean ± SEM. * P < 0.05 vs. vehicle, # P < 0.05 vs. Sema, ^ P < 0.05 vs. α-MSTN + α-ActA, + P < 0.05 vs. baseline for the last timepoint of each group. Stats by two-way RM ANOVA. α-MSTN: anti-myostatin antibody, α-ActA: anti-activin a antibody, sema: semaglutide, DXA dual energy x-ray absorptiometry.