Long-term hyperglycaemia decreases gastrocnemius susceptibility to permeability transition.

BACKGROUND

Hyperglycaemia-resulting in mitochondrial bioenergetics' complications is associated with skeletal muscle dysfunction. The aim of this work was to analyse the effect of long-term severe hyperglycaemia on gastrocnemius mitochondrial bioenergetics, with special relevance on the susceptibility to mitochondrial permeability transition pore (MPTP) opening.

METHODS

Sixteen adult (6- to 8-week-old) male Wistar rats were randomly divided into two groups (n = 8/group): control and diabetic. A single dose (50 mg kg(-1)) of streptozotocin (STZ) was administrated i.p. to induce hyperglycaemia. In vitro mitochondrial oxygen consumption rates, membrane potential (Delta psi) fluctuations, MPTP induction as followed by osmotic swelling and extramitochondrial calcium movements and caspase 9-like activity were evaluated 18 weeks after STZ treatment.

RESULTS

STZ treatment induced an increase in state 4 and a decrease in the respiratory control ratio with complex I substrates (P < 0.05), whereas no differences were observed using complex II substrates. In both conditions, no significant differences were observed when measuring maximal Delta psi, although STZ treatment increased Delta psi during ADP-induced depolarization when succinate was used. The most critical result was that muscle mitochondria isolated from STZ-treated rats showed a decrease susceptibility to MPTP induction by calcium, as followed by two different experimental protocols. Interestingly, the protection was accompanied by a decrease in muscle caspase 9-like activity.

CONCLUSIONS

These data demonstrate that 18 weeks of STZ treatment lead to a decrease in gastrocnemius mitochondrial respiratory control ratio and to decreased calcium-dependent mitochondrial MPTP. Results from this and other works suggest that mitochondrial effects of hyperglycaemia are time and organ specific.