Fructose intake is linked with the increasing prevalence of
insulin resistance and there is now evidence for a specific
insulin-resistant
cardiomyopathy. The aim of this study was to determine the cardiac-specific myocardial remodeling effects of high
fructose dietary intake. Given the links between
insulin signaling,
reactive oxygen species generation and autophagy induction, we hypothesized that autophagy contributes to pathologic remodeling in the
insulin-resistant heart, and in particular may be a feature of high
fructose diet-induced cardiac phenotype. Male C57Bl/6 mice were fed a high
fructose (60%) diet or nutrient-matched control diet for 12 weeks. Systemic and myocardial
insulin-resistant status was characterized.
Superoxide production (
lucigenin) and cellular growth and death signaling pathways were examined in myocardial tissue. Myocardial structural remodeling was evaluated by measurement of heart weight indices and histological analysis of
collagen deposition (
picrosirius red).
Fructose-fed mice exhibited
hyperglycemia and
glucose intolerance, but plasma
insulin and blood pressure were unchanged. High
fructose intake suppressed the myocardial Akt cell survival signaling coincident with increased cardiac
superoxide generation (21% increase, p<0.05).
Fructose feeding induced elevated autophagy (LC3B-II: LC3B-I ratio: 46% increase, p<0.05) but not apoptosis signaling (unchanged Bax-1:Bcl-2 ratio). Despite a 28% increase in interstitial
fibrosis, no difference in heart weight was observed in
fructose-fed mice. We provide the first evidence that myocardial autophagy activation is associated with systemic
insulin resistance, and that high level
fructose intake inflicts direct cardiac damage. Upregulated autophagy is associated with elevated cardiac
superoxide production, suppressed cell survival signaling and fibrotic infiltration in
fructose-fed mice. The novel finding that autophagy contributes to cardiac pathology in
insulin resistance identifies a new therapeutic target for
diabetic cardiomyopathy.