Acetaminophen influences musculoskeletal signaling but not adaptations to endurance exercise training

Abstract

Acetaminophen (ACE) is a widely used analgesic and antipyretic drug with various applications, from pain relief to fever reduction. Recent studies have reported equivocal effects of habitual ACE intake on exercise performance, muscle growth, and risks to bone health. Thus, this study aimed to assess the impact of a 6‐week, low‐dose ACE regimen on muscle and bone adaptations in exercising and non‐exercising rats. Nine‐week‐old Wistar rats (n = 40) were randomized to an exercise or control (no exercise) condition with ACE or without (placebo). For the exercise condition, rats ran 5 days per week for 6 weeks at a 5% incline for 2 min at 15 cm/s, 2 min at 20 cm/s, and 26 min at 25 cm/s. A human equivalent dose of ACE was administered (379 mg/kg body weight) in drinking water and adjusted each week based on body weight. Food, water intake, and body weight were measured daily. At the beginning of week 6, animals in the exercise group completed a maximal treadmill test. At the end of week 6, rats were euthanized, and muscle cross‐sectional area (CSA), fiber type, and signaling pathways were measured. Additionally, three‐point bending and microcomputer tomography were measured in the femur. Follow‐up experiments in human primary muscle cells were used to explore supra‐physiological effects of ACE. Data were analyzed using a two‐way ANOVA for treatment (ACE or placebo) and condition (exercise or non‐exercise) for all animal outcomes. Data for cell culture experiments were analyzed via ANOVA. If omnibus significance was found in either ANOVA, a post hoc analysis was completed, and a Tukey's adjustment was used. ACE did not alter body weight, water intake, food intake, or treadmill performance (p > .05). There was a treatment‐by‐condition effect for Young's Modulus where placebo exercise was significantly lower than placebo control (p < .05). There was no treatment by condition effects for microCT measures, muscle CSA, fiber type, or mRNA expression. Phosphorylated‐AMPK was significantly increased with exercise (p < .05) and this was attenuated with ACE treatment. Furthermore, phospho‐4EBP1 was depressed in the exercise group compared to the control (p < .05) and increased in the ACE control and ACE exercise group compared to placebo exercise (p < .05). A low dose of ACE did not influence chronic musculoskeletal adaptations in exercising rodents but acutely attenuated AMPK phosphorylation and 4EBP1 dephosphorylation post‐exercise.

Editorial: Decoding muscle adaptation through skeletal muscle negative data: understanding the signaling factors involved

“…Skeletal muscle adapts to exercise by improving metabolism and structure, leading to elevated performance. The identification of multiple signaling pathways that contribute to muscle adaptation including, but not limited to, JAK2/STAT3 ( Yao et al, 2024 ), TGFβ-Smad2/3-ATF4 ( Vanhoutte et al, 2024 ), Hippo/YAP ( Pan et al, 2024 ), Ca (2+)-NFATC1 ( Zhou et al, 2024a ), PROKR1-CREB-NR4A2 ( Mok et al, 2024 ), mitochondria cross talk ( Reisman et al, 2024 ), mitochondria biogenesis and function ( Mesquita et al, 2021 ; Marzetti et al, 2024 ), redox levels ( Zhou et al, 2024b ), and autophagy ( Parousis et al, 2018 ), and also individual mediators like GADD42a ( Marcotte et al, 2023 ), Trim63 ( da Mata et al, 2024 ), mTORC1 ( DHulst et al, 2022 ; McIntosh et al, 2023 ), YAP ( Brooks et al, 2018 ) and AMPK ( Kido et al, 2023 ; Roberts et al, 2024 ) have provided important insight into our understanding of muscle plasticity. However, signaling proteins or pathways that do not change with exercise are rarely reported and often interpreted as unimportant and therefore are not published.…”