Endurance training reverts heart mitochondrial dysfunction, permeability transition and apoptotic signaling in long-term severe hyperglycemia

The present study analyzed the effects of endurance training against cardiac mitochondrial dysfunction, particularly on the susceptibility to mitochondrial permeability transition pore (MPTP) induction in streptozotocin (STZ)-induced hyperglycemia.Twenty-four young male Wistar rats were randomly assigned into sedentary citrate (SED + CIT), sedentary type I diabetes (SED + STZ; 50 mg/kg), T + CIT (14-week treadmill running, 60 min/day) and T + STZ (injected 4 weeks before training). After 18 weeks, isolated heart mitochondria were used for in vitro oxygen consumption and transmembrane potential (∆Ψ) assessment. Cyclosporin-A (CyclA)-sensitive osmotic swelling and Ca2+ fluxes were measured to study MPTP susceptibility. Voltage-dependent anion channel (VDAC), adenine nucleotide translocator (ANT), cyclophilin D (CypD), transcription factor A (Tfam), Bax, Bcl-2 contents, caspase-3 and -9 activities were determined.In the sedentary group, long-term severe hyperglycemia decreased state 3, CCCP-induced uncoupling and increased oligomycin-inhibited respiration, state 4 and lag phase with glutamate–malate. A decreased state 3 and state 4 with succinate were observed. Moreover, hyperglycemia decreased Ca2+ uptake and increased CyclA-sensitive Ca2+ release and Ca2+-induced mitochondrial swelling. The oxygen consumption and ∆Ψ parameters impaired by long-term severe hyperglycemia were reverted by endurance training (SED + STZ vs. T + STZ). Training increased mitochondrial Ca2+ uptake and decreased Ca2+ release in hyperglycemic groups. Additionally, endurance training reverted the hyperglycemia-induced CypD elevation, attenuating decrease of ANT, VDAC and Tfam. Moreover, training prevented the STZ-induced elevation in Bax, Bax-to-Bcl-2 ratio, caspase-3 and -9 and the increased Bcl-2.Endurance training reestablished heart mitochondrial respiratory dysfunction caused by long-term severe hyperglycemia and reduced the increased susceptibility to MPTP induction probably by modulation of MPTP regulatory proteins.