Age-Dependent Changes in Metabolism, Contractile Function, and Ischemic Sensitivity in Hearts From <i>db/db</i> Mice

TLDR

The study measured glucose and palmitate metabolism and contractile function in ex vivo perfused working hearts from db/+ and db/db female mice at 6, 10–12, and 16–18 weeks, and assessed post‑ischemia‑reperfusion mechanical recovery in male hearts at 6 and 12 weeks. Diabetic db/db hearts show a progressive cardiomyopathy characterized by sustained elevation of fatty acid oxidation, progressive loss of carbohydrate oxidation, age‑dependent decline in mechanical function, and impaired post‑ischemia‑reperfusion recovery, while PPAR‑α treatment fails to improve ischemic sensitivity despite shifting substrate utilization.

Abstract

Glucose and palmitate metabolism and contractile function were measured with ex vivo perfused working hearts from control (db/+) and diabetic (db/db) female mice at 6, 10–12, and 16–18 weeks of age. Palmitate oxidation was increased by 2.2-fold in 6-week-old db/db hearts and remained elevated in 10- to 12- and 16- to 18-week-old hearts. Carbohydrate oxidation was normal at 6 weeks but was reduced to 27 and 23% of control at 10–12 and 16–18 weeks, respectively. At 6 weeks, db/db hearts exhibited a slight reduction in mechanical function, whereas marked signs of dysfunction were evident at 10–12 and 16–18 weeks. Mechanical function after ischemia-reperfusion was examined in hearts from male mice; at 6 weeks, db/db hearts showed normal recovery, whereas at 12 weeks it was markedly reduced. Fatty acid oxidation was the predominant substrate used after reperfusion. Thus, diabetic db/db hearts exhibit signs of a progressive cardiomyopathy; increased fatty acid oxidation preceded reductions in carbohydrate oxidation. Postischemic recovery of function was reduced in db/db hearts, in parallel with age-dependent changes in normoxic contractile performance. Finally, peroxisome proliferator-activated receptor-α treatment (3 weeks) did not affect sensitivity to ischemia-reperfusion, even though carbohydrate oxidation was increased and palmitate oxidation was decreased.