Regulation of KATP and Cl channel activity by AMPK, ATP and adenosine receptors: impact on membrane excitability during muscle activity and fatigue

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Noteworthy are complex changes in ion channel activity in the cell membrane during skeletal muscle activity. The first change, occurring during Phase 1, starts at the onset of muscle activity and is characterized by a 70% decreases in ClC-1 Cl- channel activity. Phase 2 occurs is characterized by large increases ClC-1 and KATP channel activity up to 3-times above the pre-stimulation level. During moderate exercise, mean interstitial [K+] reaches 10 mM within 5 min. Our studies on K+ and Cl- effects on membrane excitability are providing evidence that the reduction in ClC-1 channel activity during Phase 1 is important not only to prevent any K+-induced force depression, but in fact to augment the capacity of K+ to potentiate force at 10 mM K+. The increase in ClC-1 and KATP channel activity during Phase 2 is believed to be associated with fatigue, known as the decrease in force or work when muscles are repetitively stimulated. It is now well accepted that a major factor in muscle fatigue involves a decrease in Ca2+ release by the sarcoplasmic reticulum, which in turn is in part due to a decreased membrane excitability. The decreased excitability is triggered by increase in ClC-1 activity changing the K+ effect from a potentiation to a depression, while the increase in K+ efflux through KATP channels reduces action potential amplitude to eventually reduce force sparing ATP.***     The question is what controls the complex changes in the activity of ClC-1 and KATP channel activity from the onset of muscle activity (i.e., Phase 1) to the development of fatigue (i.e., Phase 2). It has been shown that the decrease in ClC-1 channel activity at the onset of exercise is related to a phosphorylation by PKC. It is also known that activation of ATP receptors reduce ClC-1 channel activity, but it remains to be determined whether these ATP receptors are involved at the onset of exercise. Under patch clamp conditions, the A1 adenosine receptors activate KATP channels, but it remains to be determined if the A1 receptors are involved in the activation of ClC-1 and KATP channels during fatigue. In cardiac muscle, AMPK, an important cell energy sensor, activate KATP channels; it is therefore possible that it also activates the ClC-1 and KATP channels during fatigue in skeletal muscle. ***     The long term objective is to study the intracellular signaling pathways that regulate membrane excitability from the onset of muscle activity to fatigue. The short term objectives of this proposal are to investigate i) the role of ATP and its receptors in optimizing muscle performance during Phase 1 and ii) the role of AMPK and adenosine in triggering fatigue (Phase 2). Two hypotheses are proposed: 1) "ATP receptors optimize muscle performance by lowering ClC-1 Cl- channel activity, activating Na+ K+ ATPase pump, and promoting K+-induced force potentiation" and 2) "AMPK and adenosine triggers fatigue by reducing the pump activity and activating KATP and ClC-1 channels". **