GDF11 Decreases Pressure Overload–Induced Hypertrophy, but Can Cause Severe Cachexia and Premature Death

Abstract

<div class="section"> <a class="named-anchor" id="S1"> <!-- named anchor --> </a> <h5 class="section-title" id="d597714e250">Rationale:</h5> <p id="P1">Possible beneficial effects of Growth Differentiation Factor 11 (GDF11) on the normal, diseased, and aging heart have been reported, including reversing aging induced hypertrophy. These effects have not been well validated. High levels of GDF11 have also been shown to cause cardiac and skeletal muscle wasting. These controversies could be resolved if dose-dependent effects of GDF11 were defined in normal and aged animals as well as in pressure overload induced pathological hypertrophy. </p> </div><div class="section"> <a class="named-anchor" id="S2"> <!-- named anchor --> </a> <h5 class="section-title" id="d597714e255">Objective:</h5> <p id="P2">To determine dose-dependent effects of GDF11 on normal hearts and those with pressure overload induced cardiac hypertrophy. </p> </div><div class="section"> <a class="named-anchor" id="S3"> <!-- named anchor --> </a> <h5 class="section-title" id="d597714e260">Methods and Results:</h5> <p id="P3">12–13-week-old C57BL/6 mice underwent transverse aortic constriction (TAC) surgery. One-week post TAC, these mice received recombinant GDF11 at one of 3 doses: 0.5 mg/kg, 1.0 mg/kg, or 5.0 mg/kg for up to 14 days. Treatment with GDF11 increased plasma concentrations of GDF11 and p-SMAD2 in the heart. There were no significant differences in the peak pressure gradients across the aortic constriction between treatment groups at one-week post-TAC. Two weeks of GDF11 treatment caused dose-dependent decreases in cardiac hypertrophy as measured by HW/TL ratio, myocyte cross sectional area, and LV mass. GDF11 improved cardiac pump function while preventing TAC-induced ventricular dilation and caused a dose-dependent decrease in interstitial fibrosis (in vivo), despite increasing markers of fibroblast activation and myofibroblast transdifferentiation (in vitro). Treatment with the highest dose (5.0mg/kg) of GDF11 caused severe body weight loss, with significant decreases in both muscle and organ weights and death in both sham and TAC mice. </p> </div><div class="section"> <a class="named-anchor" id="S4"> <!-- named anchor --> </a> <h5 class="section-title" id="d597714e265">Conclusions:</h5> <p id="P4">Although GDF11 treatment can reduce pathological cardiac hypertrophy and associated fibrosis while improving cardiac pump function in pressure overload, high doses of GDF11 cause severe cachexia and death. Use of GDF11 as a therapy could have potentially devastating actions on the heart and other tissues. </p> </div>