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; 50mg/kg), T+CIT (14-week treadmill running, 60min/day) and T+STZ (injected 4weeks before training). After 18weeks, isolated heart mitochondria were used for in vitro oxygen consumption and transmembrane potential (∆Ψ) assessment. Cyclosporin-A (CyclA)-sensitive osmotic swelling and Ca(2+) 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 Ca(2+) uptake and increased CyclA-sensitive Ca(2+) release and Ca(2+)-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 Ca(2+) uptake and decreased Ca(2+) 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.
Lumini-Oliveira
José
J
Research Centre in Physical Activity, Health and Leisure, Faculty of Sport, University of Porto, Portugal.
Magalhães
José
J
Pereira
Cláudia V
CV
Moreira
Ana C
AC
Oliveira
Paulo J
PJ
Ascensão
António
A
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D019069:Cell Respiration; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000503:physiopathology; D004734:Energy Metabolism; D005786:Gene Expression Regulation; D006801:Humans; D006943:Hyperglycemia / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D008564:Membrane Potentials; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D008933:Mitochondrial Swelling; D009043:Motor Activity / Q000502:physiology*; D010807:Physical Endurance / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D012720:Severity of Illness Index; D015398:Signal Transduction
D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore