Abstract 20029: Inhibition of Myostatin for the Prevention and Treatment of Cardiac Dysfunction after Aortic Constriction
Introduction: Myostatin (MSTN) is a secreted regulator of skeletal muscle growth recently recognized to increase in cardiac pathologies. MSTN inhibits the pro-survival kinase, Akt, and MSTN-null mice are protected against aging-related cardiac dysfunction and fibrosis. We hypothesized that increased cardiac MSTN is maladaptive and tested whether RAP-031, a murine analog of MSTN inhibitor (ACE-031) currently in clinical trials for skeletal muscle disease, could mitigate cardiac dysfunction after transverse aortic constriction (TAC).
Methods: To see if RAP-031 could prevent cardiac dysfunction, wild-type (WT) FVB mice were randomized to RAP-031 (10mg/kg SQ, 2x/week) or vehicle. After 1 week, groups were further randomized to TAC (27G needle) or sham operation (N=5–7). Body weight, body composition by MRI, and cardiac function were followed for 12 weeks. To evaluate if RAP-031 could treat cardiac dysfunction, WT mice underwent TAC and when fractional shortening (FS) was ≥2STD below baseline were randomized to RAP-031 or vehicle (N=4–8).
Results: Consistent with myostatin inhibition, RAP-031 pretreatment increased lean mass after TAC (6.1%±2.0) or sham operation (7.3%± 1.5) (p<0.05 vs baseline) while it was unchanged with vehicle pretreatment (p=NS vs baseline). TAC reduced FS in the vehicle-pre-treated mice vs sham (45%±6.8 vs 58%±2.7, p<0.05). In contrast, RAP-031 pretreatment prevented the TAC-mediated reduction in FS (RAP-031 TAC: 69% ±7.8 vs RAP-031 Sham: 70%± 3.2), and, in fact, resulted in better than baseline FS (p<0.05). Lung wt/Tibial length (TL) was increased in TAC'd mice pre-treated with vehicle but not those pretreated with RAP-031. Heart wt/TL was increased comparably in both groups post-TAC. In the treatment cohort, mice developed LV dysfunction 4 weeks post-TAC (p<0.05 vs baseline) at which time RAP-031 or vehicle was initiated. 12-weeks post-TAC, FS in vehicle-treated mice remained significantly reduced (45.1%±2.0) whereas FS in the RAP-031 treatment group had been restored to baseline (66.2%±2.2, p<0.05).
Conclusions: The MSTN inhibitor RAP-031 can both prevent and treat TAC-induced cardiac dysfunction in mice. Further investigation is warranted to define the potential of this novel therapeutic approach in heart failure.
- © 2010 by American Heart Association, Inc.