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Abstract
Diabetic patients develop cardiomyopathy characterized by
hypertrophy, diastolic dysfunction, and intracellular lipid accumulation,
termed lipotoxicity. Diabetic hearts utilize fatty acids as a major energy
source, which produces high levels of oxidative stress, thereby inducing
mitochondrial dysfunction. To elucidate how mitochondrial function is regulated in
diabetic
cardiomyopathy. Mice were fed either a normal diet (ND) or high fat diet (HFD, 60
kcal % fat). Although autophagic flux was activated by HFD consumption,
peaking at 6 weeks (p<0.05), it was attenuated thereafter. Mitophagy,
evaluated with Mito-Keima, was increased after 3 weeks of HFD feeding
(mitophagy area: 8.3% per cell with ND and 12.4% with HFD) and continued to
increase even after 2 months (p<0.05). By isolating adult
cardiomyocytes from GFP-LC3 mice fed HFD, we confirmed that mitochondria
were sequestrated by LC3 positive autophagosomes during mitophagy. In wild
type (WT) mice, cardiac hypertrophy, diastolic dysfunction (EDPVR =
0.051±0.009 in ND and 0.11±0.004 in HFD) and lipid
accumulation occurred within 2 months of HFD feeding (p<0.05).
Deletion of atg7 impaired mitophagy, increased lipid
accumulation, exacerbated diastolic dysfunction (EDPVR=0.11±0.004 in
WT and 0.152±0.019 in atg7 cKO, p<0.05) and
induced systolic dysfunction (ESPVR=24.86±2.46 in WT and
15.93±1.76 in atg7 cKO, p<0.05) during HFD
feeding. Deletion of Parkin partially inhibited mitophagy, increased lipid
accumulation and exacerbated diastolic dysfunction (EDPVR=0.124±0.005
in WT and 0.176±0.018 in Parkin KO, p<0.05) in response to HFD
feeding. Injection of Tat-Beclin1 (TB1) activated mitophagy, attenuated
mitochondrial dysfunction, decreased lipid accumulation, and protected
against cardiac diastolic dysfunction (EDPVR=0.110±0.009 in Control
peptide and 0.078±0.015 in TB1, p<0.05) during HFD
feeding. Mitophagy serves as an essential quality control mechanism for
mitochondria in the heart during HFD consumption. Impairment of mitophagy
induces mitochondrial dysfunction and lipid accumulation, thereby
exacerbating diabetic cardiomyopathy. Conversely, activation of mitophagy
protects against HFD-induced diabetic cardiomyopathy.