Abstract 1467: Cardiac-specific Expression of Myostatin and an Inhibitor of Myostatin Regulate Heart Size and Function in Response to Pressure Overload
Previously we have shown that Myostatin (MSTN), a negative regulator of skeletal muscle growth, is upregulated in a genetic model of cardiac hypertrophy and inhibits cardiomyocyte growth in vitro. However, MSTN−/− mice have paradoxically smaller hearts at baseline, which may reflect a developmental role of MSTN. To clarify the postnatal role of MSTN in the heart, we generated transgenic (TG) mouse lines that express MSTN and the inhibitory propeptide (dnMSTN) under the control of the α-MHC promoter to achieve cardiac-specific expression predominantly after birth. Immunoblotting confirmed expected cardiac-specific MSTN and dnMSTN protein expression in each line. At baseline the heart weight/tibial length (HW/TL) of MSTN TG mice showed a 6.9±1.7% (p=0.03, n=8) reduction versus non-transgenic (NTG) mice, while the HW/TL of dnMSTN TG mice was increased 13.6±1.31% (p<0.001, n=35). This increase in HW/TL was accompanied by an increase in p38 phosphorylation, consistent with our previously published results showing MSTN blocked hypertrophy in a p38-dependent manner. In order to determine if MSTN regulates pressure overload-induced hypertrophy we subjected mice to trans-aortic constriction (TAC) for 14 days. The growth response to TAC was similar between NTG (32.9±0.97%, p<0.01, n=7) and dnMSTN TG (35.6±5.9%, p<0.01, n=7) but interestingly the growth response to TAC was blunted in MSTN TG mice (19.2±3.5%, p<0.001, n=8) compared to NTG. To determine if MSTN effects heart function we performed unanesthetized echocardiography. No difference in heart function between both MSTN and dnMSTN TG mice compared to NTG at baseline. After 13 weeks of TAC dnMSTN TG mice showed better fractional shortening (60.7±3.1%, p<0.05, n=3) compared to NTG (48.5±2.7%, n=3) suggesting that the inhibition of MSTN during chronic pressure overload may be beneficial to heart function. Chronic TAC studies with MSTN TG mice are ongoing. These data support the hypothesis that MSTN is a negative regulator of post-natal cardiac growth and that the smaller hearts seen in MSTN−/− mice may reflect developmental confounders. Additionally, these studies suggest that inhibition of MSTN in heart failure may improve cardiac function.
This research has received full or partial funding support from the American Heart Association, AHA Founders Affiliate (Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, Vermont).