Altered Skeletal Muscle Phosphate Metabolism After Muscle Damage Is Associated With Elevated Effort Perception During Exercise in Humans

It remains unclear why exercising damaged muscles is perceived as disproportionately more effortful. Given the known role of inorganic phosphate (Pi) in fatigue and afferent sensory signaling, we tested whether muscle damage disrupts phosphate metabolism and whether this is associated with heightened ratings of perceived exertion (RPE). Eighteen adults (23 ± 4 years) completed assessments before and 48 h after muscle damage induced by unilateral eccentric knee extensions (EIMD); the contralateral leg served as control. Magnetic resonance imaging quantified quadriceps cross‐sectional area (Qcsa) and 31 P‐MR spectroscopy quantified Pi, phosphocreatine (PCr), Pi/PCr, ATPγ and pH at rest, during knee‐extension exercise, and recovery. RPE was recorded throughout exercise. At 48 h, the EIMD leg showed increased soreness (17‐fold), reduced maximum voluntary contraction (−18.4% ± 3.8%) and increased Qcsa (+2.8% ± 0.4%; mean individual percentage changes ± SEM; p < 0.001). Visit × condition interactions were observed for Pi, Pi/PCr, and ATPγ at rest (ηp 2 = 0.31–0.35) and across rest, exercise and recovery (ηp 2 = 0.66–0.78), but not for PCr or pH. This reflected sustained elevations of Pi and Pi/PCr, and lower ATPγ in the EIMD leg alongside higher RPE at 48 h. Elevated resting Pi/PCr was strongly associated with elevated RPE ( r = 0.856, p < 0.001), whereas exercise‐induced Pi/PCr changes were not associated with RPE. Overall, EIMD causes a sustained disturbance in muscle phosphate homeostasis that is strongly associated with elevated RPE. These findings provide new evidence linking resting muscle phosphate‐metabolic disturbance with heightened effort perception after damage.