Key result
Targeted deletion of Gdf11 in cardiomyocytes did not cause cardiac hypertrophy but led to left ventricular dilation compared with control mice.
Why the study?
Active GDF11 can reduce cardiac hypertrophy in aged mice and low serum levels predict morbidity and mortality in coronary patients, prompting testing of whether cardiac-specific Gdf11 deficiency leads to cardiac hypertrophy in young adulthood.
Does cardiac-specific Gdf11 deficiency lead to cardiac hypertrophy or left ventricular dilation in young mice?
Does cardiac-specific Gdf11 deficiency lead to cardiac hypertrophy or left ventricular dilation in young mice?
Targeted deletion of Gdf11 in cardiomyocytes may lead to left ventricular dilation without hypertrophy, but the Myh6-cre mouse model presents significant confounding toxicity that complicates interpretation.
May indicate Gdf11 prevents LV dilation without hypertrophy in mice; leaves open translation amid Myh6-cre toxicity.
Administration of active growth differentiation factor 11 (GDF11) to aged mice can reduce cardiac hypertrophy, and low serum levels of GDF11 measured together with the related protein, myostatin (also known as GDF8), predict future morbidity and mortality in coronary heart patients. Using mice with a loxP-flanked (“floxed”) allele of Gdf11 and Myh6-driven expression of Cre recombinase to delete Gdf11 in cardiomyocytes, we tested the hypothesis that cardiac-specific Gdf11 deficiency might lead to cardiac hypertrophy in young adulthood. We observed that targeted deletion of Gdf11 in cardiomyocytes does not cause cardiac hypertrophy but rather leads to left ventricular dilation when compared with control mice carrying only the Myh6-cre or Gdf11-floxed alleles, suggesting a possible etiology for dilated cardiomyopathy. However, the mechanism underlying this finding remains unclear because of multiple confounding effects associated with the selected model. First, whole heart Gdf11 expression did not decrease in Myh6-cre; Gdf11-floxed mice, possibly because of upregulation of Gdf11 in noncardiomyocytes in the heart. Second, we observed Cre-associated toxicity, with lower body weights and increased global fibrosis, in Cre-only control male mice compared with flox-only controls, making it challenging to infer which changes in Myh6-cre;Gdf11-floxed mice were the result of Cre toxicity versus deletion of Gdf11. Third, we observed differential expression of cre mRNA in Cre-only controls compared with the cardiomyocyte-specific knockout mice, also making comparison between these two groups difficult. Thus, targeted Gdf11 deletion in cardiomyocytes may lead to left ventricular dilation without hypertrophy, but alternative animal models are necessary to understand the mechanism for these findings. NEW & NOTEWORTHY We observed that targeted deletion of growth differentiation factor 11 in cardiomyocytes does not cause cardiac hypertrophy but rather leads to left ventricular dilation compared with control mice carrying only the Myh6-cre or growth differentiation factor 11-floxed alleles. However, the mechanism underlying this finding remains unclear because of multiple confounding effects associated with the selected mouse model.
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Garbern et al. (2019) studied Cardiac hypertrophy and dilated cardiomyopathy. Targeted deletion of Gdf11 in cardiomyocytes vs. Control mice carrying only the Myh6-cre or Gdf11-floxed alleles was evaluated on Cardiac hypertrophy and left ventricular dilation. Targeted deletion of Gdf11 in cardiomyocytes did not cause cardiac hypertrophy but led to left ventricular dilation compared with control mice.
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