The influence of biological sex on the relationship between inorganic phosphates, hydrogen ions, and the peripheral component of neuromuscular fatigue
Authors: Laginestra Fabio Giuseppe , Broxterman Ryan , Iannetta Danilo , Kofoed Jason , Craig Jesse , Lewis Matthew , Jeong Eun-Kee 
Published: May 2024

Background: In males, the relationship between peripheral fatigue development and intramuscular inorganic phosphate (Pi) accumulation is more robust than that with hydrogen ion (H+) accumulation. Based on previous findings of greater peripheral fatigability during exercise in males vs females (as pre-post %changes in twitch force, Qtw) and thus the potential for sex differences in the mechanisms of fatigue, we aimed to: 1) establish whether the relationship between peripheral fatigue development and Pi accumulation is more robust than that with H+ accumulation in females, and 2) determine whether females and males differ in the development of peripheral fatigue for a given Pi or H+ accumulation. Methods: Eleven recreationally active, healthy, young individuals (5 females) performed two consecutive (interspersed by 5-min of rest) intermittent isometric single-leg knee-extensor trials (60 maximal voluntary contractions; 3-s contraction, 2-s relaxation). Throughout both trials, quadriceps intramuscular [Pi] and [H+] were quantified using phosphorus magnetic resonance spectroscopy (31P-MRS), and quadriceps Qtw was measured using electrical femoral nerve stimulation. Peripheral fatigue was quantified as the exercise-induced decrease in Qtw. The relationships between Qtw and [Pi] and [H+] were analyzed using linear mixed-effects models for the portion of exercise where peripheral fatigue was developing ( i.e., decreasing Qtw). The results are presented as the Z-score β coeffcients and p-values. Results: The exercise-induced reduction in Qtw (thus peripheral fatigue) was larger in males compared to females (-65±16 vs -43±21%; p<0.05). During both trials, the decrease in Qtw for a given increase in [Pi] was not different between sexes, and these relationships were not altered from Trial 1 to Trial 2 (Female slope Trial 1: -1.5 vs Trial 2: -1.4; Male slope Trial 1: -1.7 vs Trial 2: -1.6, all p>0.3). The decrease in Qtw for a given increase in [H+] was greater for men compared to women in both trials (both p<0.01), and these relationships were not altered from Trial 1 to Trial 2 (both p>0.4) (Female slope Trial 1: -0.8 vs Trial 2: -0.9; Male slope Trial 1: -1.2 vs Trial 2: -1.3). The overall relationship ( i.e., y-intercept) between Qtw and [Pi] did not shift up or down across the consecutive trials for either sex (Females y-intercept Trial 1: -1.0 vs Trial 2: -1.3; Males y-intercept Trial 1: 0.8 vs Trial 2: 0.7, both p>0.2). In contrast, the overall relationship ( i.e., y-intercept) between Qtw and [H+] shifted down from Trial 1 to Trial 2 for both sexes (Females y-intercept Trial 1: 0.2 vs Trial 2: -0.3; Males y-intercept Trial 1: 0.3 vs Trial 2: -0.2, both p<0.01). Conclusions: In males and females, the relationship between the magnitude of Qtw and Pi is more robust compared to the relationship between the magnitude of Qtw and H+, suggesting Pi accumulation as the stronger mediator of peripheral fatigue in both sexes. Furthermore, the susceptibility of Qtw to decrease in response to a given increase in Pi was not different between sexes. The difference in peripheral fatigability between males and females are therefore likely due to differences in [Pi] and factors determining the magnitude of its accumulation ( e.g., force output, muscle fiber type distribution, or O2 transport and utilization). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.