K_ATP channel deficiency in mouse FDB causes an impairment of energy metabolism during fatigue

Abstract

The skeletal muscle ATP-sensitive K (K) channel is crucial in preventing fiber damage and contractile dysfunction, possibly by preventing damaging ATP depletion. The objective of this study was to investigate changes in energy metabolism during fatigue in wild-type and inwardly rectifying K channel (Kir6.2)-deficient (Kir6.2) flexor digitorum brevis (FDB), a muscle that lacks functional K channels. Fatigue was elicited with one tetanic contraction every second. Decreases in ATP and total adenylate levels were significantly greater in wild-type than Kir6.2 FDB during the last 2 min of the fatigue period. Glycogen depletion was greater in Kir6.2 FDB for the first 60 s, but not by the end of the fatigue period, while there was no difference in glucose uptake. The total amount of glucosyl units entering glycolysis was the same in wild-type and Kir6.2 FDB. During the first 60 s, Kir6.2 FDB generated less lactate and more CO; in the last 120 s, Kir6.2 FDB stopped generating CO and produced more lactate. The ATP generated during fatigue from phosphocreatine, glycolysis (lactate), and oxidative phosphorylation (CO) was 3.3-fold greater in Kir6.2 than wild-type FDB. Because ATP and total adenylate were significantly less in Kir6.2 FDB, it is suggested that Kir6.2 FDB has a greater energy deficit, despite a greater ATP production, which is further supported by greater glucose uptake and lactate and CO production in Kir6.2 FDB during the recovery period. It is thus concluded that a lack of functional K channels results in an impairment of energy metabolism.

Characterization and utilization of the flexor digitorum brevis for assessing skeletal muscle function

“…An optimum voltage of 20 V was established prior to the experiments to ensure maximal stimulation of the FDB, EDL, and soleus (data not shown). Absolute muscle force data were converted to specific force (N/cm 2 ) using previously described equations for the mathematical estimation of muscle CSA [ 18 ] and physiological cross-sectional area (PCSA) [ 19 ]. The primary difference between CSA and PCSA is the inclusion of the muscle fiber length to muscle length ratio in the PCSA equation.…”

Hearts lacking plasma membrane KATP channels display changes in basal aerobic metabolic substrate preference and AMPK activity

“…However, it has been also shown that K ATP channel-mediated cardioprotection can occur even when action potential shortening is prevented (20) and leads to high-energy phosphate preservation (40) and that K ATP channels play a role in maintaining high-energy phosphates in heart failure (28). With respect to other muscle types, a recent study (49) has shown that metabolism becomes dysfunctional during fatigue in skeletal muscle from Kir6.2 Ϫ/Ϫ mice, although there are likely differences in the role of K ATP channels between cardiac and skeletal muscle, as other groups have shown that Kir6.2 ablation increases lactate and glucose uptake under nonstressed ex vivo condi- Ϫ hearts relative to Kir6.2 ϩ/ϩ hearts (n ϭ 8 hearts/group). C: histological analysis using periodic acid-Schiff stain showed a significantly higher number of glycogen particles in Kir6.2 Ϫ/Ϫ hearts relative to Kir6.2 ϩ/ϩ hearts (n ϭ 3 hearts/group).…”

“…Regarding metabolism, K ATP channel openers have previously been shown to preserve myocardial ATP content (40) during ischemic stress, perhaps by interactions with metabolic signaling pathways. Moreover, recent studies have shown altered metabolism in skeletal muscle from Kir6.2 Ϫ/Ϫ tissue (49) and that functional K ATP channels are critical in maintaining high-energy phosphates in the failing heart (28). Proteomic analysis has revealed that cardiac K ATP channels are associated with many proteins, especially those involved in glucose oxidation, fatty acid oxidation, glycolysis (29), and other metabolism pathways (29,59).…”

Changes in myoplasmic Ca2+during fatigue differ between FDB fibers, between glibenclamide-exposed and Kir6.2-/-fibers and are further modulated by verapamil

“…In fact, daily O2 uptake is greater in Kir6.2 ‐/‐ than in wild‐type mice (Alekseev et al. ; Scott ) and mitochondrial glucose oxidation increases within 60 sec during fatigue in Kir6.2 ‐/‐ FDB bundles and only during recovery in wild‐type bundles (Scott ). So, one compensatory mechanism may be a greater ATP production associated with greater oxidative capacity that reduces the dependency of Kir6.2 ‐/‐ fibers on the myoprotection of KATP channels.…”

“…Another possibility to explain the differences between Kir6.2 -/and glibenclamide-exposed fibers is the fact that Kir6.2 -/represents a chronic loss of KATP channel activity that allows for compensatory mechanisms to develop. In fact, daily O2 uptake is greater in Kir6.2 -/than in wild-type mice (Alekseev et al 2010;Scott 2012) and mitochondrial glucose oxidation increases within 60 sec during fatigue in Kir6.2 -/-FDB bundles and only during recovery in wild-type bundles (Scott 2012). So, one compensatory mechanism may be a greater ATP production associated with greater oxidative capacity that reduces the dependency of Kir6.2 -/fibers on the myoprotection of KATP channels.…”