Long-term hyperglycaemia decreases gastrocnemius susceptibility to permeability transition

Abstract

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 (Δπ) 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 Δπ, although STZ treatment increased Δπ 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. © 2010 Stichting European Society for Clinical Investigation Journal Foundation.