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Published on: June 14, 2016
GDF11 does not rescue aging-related pathological hypertrophy
Shavonn C Smith1, Xiaoxiao Zhang1, Xiaoying Zhang1
1From the Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA (S.C.S., Xiaoxiao Zhang, Xiaoying Zhang, P.G., T.S., S Mohsin, X.G., A.S., X.C., S.R.H.); and Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT (M.F., P.G., D.H., M.M., J.K., J.T., S.M.W., A.K., S. MacDonnell).
Insights
This study found no evidence of age-related cardiac hypertrophy in healthy old mice. Restoring Growth Differentiation Factor 11 (GDF11) levels did not improve cardiac structure or function in aged mice.
Area of Science:
- Cardiovascular Biology
- Aging Research
- Molecular Medicine
Background:
- Growth Differentiation Factor 11 (GDF11) is a secreted factor implicated in aging.
- Previous research suggested GDF11 levels decline with age and contribute to pathological cardiac hypertrophy (PCH).
- Restoring GDF11 was proposed to rescue age-related cardiac dysfunction.
Purpose of the Study:
- To investigate if GDF11 administration can rescue aging-dependent PCH.
- To elucidate the underlying mechanisms of GDF11's potential effects on cardiac aging.
Main Methods:
- Old C57BL/6 mice received daily injections of recombinant GDF11 or vehicle for 28 days.
- Cardiac structure, function, and myocyte size were assessed.
- In vitro studies examined GDF11's effect on neonatal rat ventricular myocytes exposed to phenylephrine.
Main Results:
- GDF11 treatment did not alter heart weight, body weight, or heart weight/body weight ratios in old mice.
- No significant differences were observed in PCH markers, ejection fraction, or ventricular dimensions.
- In vitro, GDF11 did not reduce but rather induced hypertrophy in neonatal rat ventricular myocytes.
Conclusions:
- Healthy 24-month-old mice do not exhibit age-related PCH.
- Restoring GDF11 levels in old mice had no beneficial effect on cardiac structure or function.
- GDF11 may not be a viable therapeutic target for age-related cardiac hypertrophy.
Rationale:
Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor-β super family of secreted factors. A recent study showed that reduced GDF11 blood levels with aging was associated with pathological cardiac hypertrophy (PCH) and restoring GDF11 to normal levels in old mice rescued PCH.
Objective:
To determine whether and by what mechanism GDF11 rescues aging dependent PCH.
Methods And Results:
Twenty-four-month-old C57BL/6 mice were given a daily injection of either recombinant (r) GDF11 at 0.1 mg/kg or vehicle for 28 days. rGDF11 bioactivity was confirmed in vitro. After treatment, rGDF11 levels were significantly increased, but there was no significant effect on either heart weight or body weight. Heart weight/body weight ratios of old mice were not different from 8- or 12-week-old animals, and the PCH marker atrial natriuretic peptide was not different in young versus old mice. Ejection fraction, internal ventricular dimension, and septal wall thickness were not significantly different between rGDF11 and vehicle-treated animals at baseline and remained unchanged at 1, 2, and 4 weeks of treatment. There was no difference in myocyte cross-sectional area rGDF11 versus vehicle-treated old animals. In vitro studies using phenylephrine-treated neonatal rat ventricular myocytes, to explore the putative antihypertrophic effects of GDF11, showed that GDF11 did not reduce neonatal rat ventricular myocytes hypertrophy, but instead induced hypertrophy.
Conclusions:
Our studies show that there is no age-related PCH in disease-free 24-month-old C57BL/6 mice and that restoring GDF11 in old mice has no effect on cardiac structure or function.
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