Can a chloride channel blocker mitigate muscle fatigue?

Abstract

Muscle fatigue is a complex phenomenon defined as a temporary, exercise-induced reduction in the capacity of the muscle to produce force. Briefly summarizing (see review by Allen et al. 2008), within the muscle, fatigue can be broadly attributed to three mechanisms: reduced Ca2+ release from the sarcoplasmic reticulum (SR), reduced myofibrillar Ca2+ sensitivity, or reduced force produced per crossbridge. During extended muscular activity, metabolic by-products accumulate, and several of these metabolites are postulated to be involved in the reduced force output observed during fatigue. Inorganic phosphate (Pi), the by-product of ATP hydrolysis, is thought to contribute to fatigue via all three mechanisms. At the myofibrillar level Pi affects the myosin power-stroke, resulting in early crossbridge dissociation and promoting a transition from a strong to weak actin-myosin binding state. This results in a lower number of crossbridges in force-producing states, lower average force per crossbridge, and a reduced sensitivity of the contractile proteins to Ca2+, altogether impairing force output. Pi can also interfere with the Ca2+ signal itself. Pi can enhance Ca2+ release by activating the ryanodine receptor (RyR) via an active site on the sarcoplasm side of the SR. Pi may also diminish Ca2+ release by reducing the amount of Ca2+ available to be released from the SR. This could be accomplished by impairing Ca2+ reuptake by the sarco-endoplasmic reticulum Ca2+-ATPase (SERCA), and/or by forming a precipitate with Ca2+ (CaPi) within the SR (Fryer et al. 1995). The focus of the paper by Ferreira et al. (2021,) recently published in The Journal of Physiology, aimed to elucidate the mechanism by which Pi enters the SR.