Insulin resistance impaired Akt1 translocation to mitochondria in myocardium and contributed to diabetic cardiomyopathy (DCM). It is unknown whether activation of mitochondrial Akt in cardiac muscle can protect against DCM. To this end, we generated an inducible heart-specific transgenic mice with a mitochondria-targeting constitutively active Akt (CAMCAKT). A high fat-high fructose (HFF) diet induced myocardial fibrosis and heart failure, but cardiomyopathy was reversed in the CAMCAKT mice, indicating a mechanistic role of mitochondrial Akt1 signaling in DCM. RNAseq analysis revealed myocardial transcriptome changes, including suppressed Col1a1 and Col3a1 expression (fibrosis markers) recapitulating the mechanism of fibrosis. Accompanying lowered GP6 expression suggested a reduction in collagen-induced platelet activation. Pathway analysis revealed significant inhibition in multiple steps of melatonin degradation. Enhancing melatonin signaling, an emerging myocardial protective factor that reduces oxidative stress/apoptosis, is a novel mechanism through which mitochondrial Akt1 could protect against DCM. Under the HFF diet, cardiac mitochondrial Akt1 signaling also caused whole body changes; CAMCAKT mice had 15% less body fat, 30% lower total cholesterol and 42% lower LDL (p<0.05), and showed higher energy expenditure during night cycles and an elevated RER, an indicator for increased carbohydrate metabolism. The diet-induced fatty liver in the CAMCAKT mice was significantly lowered, suggesting that cardiac mitochondrial Akt signaling could remotely modulate hepatic fat metabolism. Liver RNAseq revealed that cholesterol synthesis in the liver was modulated by cardiac mitochondria.

In summary, activating cardiac mitochondrial Akt1 protected against DCM by inhibiting melatonin degradation, and attenuated the development of fatty liver by regulating cholesterol synthesis.


A. Ta: None. Y. Chen: None. Y. Chen: None. H.Y.H. Lin: None. P.H. Wang: Board Member; Self; Dianavi.


National Institutes of Health (R01HL096987)

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