Can a chloride channel blocker mitigate muscle fatigue?

Muscle fatigue is a complex phenomenon defined as temporary, exercise-induced reduction in the capacity of muscle to produce force. Briefly summarizing (see review by Allen et al. 2008), within muscle, can be broadly attributed three mechanisms: reduced Ca2+ release from sarcoplasmic reticulum (SR), myofibrillar sensitivity, or force produced per crossbridge. During extended muscular activity, metabolic by-products accumulate, and several these metabolites are postulated involved output observed during fatigue. Inorganic phosphate (Pi), by-product ATP hydrolysis, thought contribute via all mechanisms. At level Pi affects myosin power-stroke, resulting early crossbridge dissociation promoting transition strong weak actin-myosin binding state. This results lower number crossbridges force-producing states, average crossbridge, sensitivity contractile proteins Ca2+, altogether impairing output. also interfere with signal itself. enhance activating ryanodine receptor (RyR) an active site on sarcoplasm side SR. may diminish reducing amount available released could accomplished reuptake sarco-endoplasmic Ca2+-ATPase (SERCA), and/or forming precipitate (CaPi) SR (Fryer 1995). The focus paper Ferreira (2021,) recently published Journal Physiology, aimed elucidate mechanism which enters Anion channels considered entry point for into and, based prior speculation, (2021) tested hypothesis that through chloride (ClC). To this end, they measured free concentration intact ([Ca2+]SR) chemically permeabilized fibres Rana catesbeiana pipiens semitendinosus muscles. spark frequency was used indirect indicator [Ca2+]SR assessed using Rhod-2 Fluo-3 fluorescence at varying [Pi]. Direct measurements were made fluorescent dyes Mag-Indo-1 Fluo-5N. They found increased above baseline (0 mm Pi) when concentrations ([Pi]) below 10 mm, but expected, further increases [Pi] greatly [Ca2+]SR. Next, experiments repeated introduction 9-anthracenecarboxylic acid (9AC), known ClC blocker. 9AC prevented increase sub-10 hypothesized, attenuated decreases higher authors concluded block Pi, precipitation work exciting step forward our understanding processes have implications scenarios disease ageing, exacerbate effects putative pathway mediated CaPi summarized Fig. 1. While blocking ClCs indeed seems inhibit high [Pi], physiological relevance has not been fully established. It notable frogs housed approximately same temperature single fibre (?20°C). As result, there clear potential frog muscles under conditions. cannot currently said mammalian studies examining we aware performed temperatures well muscle. specific salts formed identified, warmer precipitation. For example, CaHPO4 becomes more soluble increased, whereas CaHPO4.2H2O less (Wang & Nancollas, 2008). Adding uncertainty, affect relationship between pH solubility. Additionally, play integral role maintaining cell excitability, blockade causes myotonia-like well-rested (Van Lunteren 2011). therefore prudent clearly demonstrate compromises contractility fatiguing conditions before exploring pharmacological interventions. We must consider what proportion response attributable SR, whether it depends type duration activity. rapidly onset activity [Ca2+] initially decreasing later dropped substantially (Allen A reasonable explanation discrepancy adenosine nucleotides opening ClCs, having greater effect than ADP, ADP AMP limit passage until However, al.’s use 5 their solutions suggests enter even any negative inotropic overcome factors release. (Ferreira 2021) illustration point. decrease probably different Although present limited data ?150% reported 30% 011504c seen Table 2. departure proportionality reconcilable Pi-mediated activation RyR decline appears caused inside blocker changes frequency. small its own, other blockers (4’4’-diisothiocyanatostilbene-2’2’-di-sulfonic 4-acetamido-4’-isothiocyanato-stilbene-2,2’-disulfonic acid) large frequency, activate (or interact closely with) Pi-binding cytosolic way prevents reaching regulatory site. indicate Pi-induced declines distinct inhibition ClC; fact carefully acknowledged (2021). Thus, transporters aside important conduits Pi-activation did prevent should preclude notion mitigate high. vary effectiveness against types anion channels, exploration variability help determine access point(s) provided compelling evidence mitigated 9AC. since ClC, conceivably another 9AC-sensitive pathway. Finally, significance remains unresolved No competing interests declared. All approved final version manuscript agree accountable aspects work. persons designated qualify authorship, those who authorship listed. None.