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Cited by 100Cardiovascular and exercise physiologyMuscle activation and electromyography studiesMuscle metabolism and nutrition

On the role of skeletal muscle acidosis and inorganic phosphates as determinants of central and peripheral fatigue: A 31P‐MRS study

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Hureau, Thomas J., Broxterman, Ryan M., Weavil, Joshua C., Lewis, Matthew T., Layec, Gwenael, Amann, Markus·2022·The Journal of Physiology
DOI 10.1113/jp283036PMC PMC9250628
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Abstract

Intramuscular hydrogen ion (H+) and inorganic phosphate (Pi) concentrations were dissociated during exercise to challenge their relationships with peripheral and central fatigue in vivo. Ten recreationally active, healthy men (27 ± 5 years; 180 ± 4 cm; 76 ± 10 kg) performed two consecutive intermittent isometric single‐leg knee‐extensor trials (60 maximal voluntary contractions; 3 s contraction, 2 s relaxation) interspersed with 5 min of rest. Phosphorus magnetic resonance spectroscopy (31 P‐MRS) was used to continuously quantify intramuscular [H+] and [Pi] during both trials. Using electrical femoral nerve stimulation, quadriceps twitch force (Qtw) and voluntary activation (VA) were quantified at rest and throughout both trials. Decreases in Qtw and VA from baseline were used to determine peripheral and central fatigue, respectively. Qtw was strongly related to both [H+] (β coefficient: −0.9, P < 0.0001) and [Pi] (−1.1, P < 0.0001) across trials. There was an effect of trial on the relationship between Qtw and [H+] (−0.5, P < 0.0001), but not Qtw and [Pi] (0.0, P = 0.976). This suggests that, unlike the unaltered association with [Pi], a given level of peripheral fatigue was associated with a different [H+] in Trial 1 vs. Trial 2. VA was related to [H+] (−0.3, P < 0.0001), but not [Pi] (−0.2, P = 0.243), across trials and there was no effect of trial (−0.1, P = 0.483). Taken together, these results support intramuscular Pi as a primary cause of peripheral fatigue, and muscle acidosis, probably acting on group III/IV muscle afferents in the interstitial space, as a contributor to central fatigue during exercise. image Key points: We investigated the relationship between intramuscular metabolites and neuromuscular function in humans performing two maximal, intermittent, knee‐extension trials interspersed with 5 min of rest. Concomitant measurements of intramuscular hydrogen (H+) and inorganic phosphate (Pi) concentrations, as well as quadriceps twitch‐force (Qtw) and voluntary activation (VA), were made throughout each trial using phosphorus magnetic resonance spectroscopy (31 P‐MRS) and electrical femoral nerve stimulations. Although [Pi] fully recovered prior to the onset of the second trial, [H+] did not. Qtw was strongly related to both [H+] and [Pi] across both trials. However, the relationship between Qtw and [H+] shifted leftward from the first to the second trial, whereas the relationship between Qtw and [Pi] remained unaltered. VA was related to [H+], but not [Pi], across both trials. These in vivo findings support the hypotheses of intramuscular Pi as a primary cause of peripheral fatigue, and muscle acidosis, probably acting on group III/IV muscle afferents, as a contributor to central fatigue.

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  • Fatigue and muscle soreness during intense exercise are typically driven by the accumulation of hydrogen ions (H+) and inorganic phosphate (Pi), which reduces pH, can impair muscle contraction and energy production, leading to both peripheral and central fatigue.

    “Fatigue and muscle soreness, typically driven by the accumulation of hydrogen ions (H+) and inorganic phosphate (Pi) during intense exercise, which reduces pH, can impair muscle contraction and energy production, leading to both peripheral and central fatigue [181,182].”

    From Global consensus on optimal exercise recommendations for enhancing healthy longevity in older adults (ICFSR) (2025) · cites this paper as [181]

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  1. Westerblad H (2021). Biochemical mechanisms of muscle fatigue. In Fatigue as a limitation to performance symposium. Madrid, Spain.

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Authors
Hureau, T. J., Broxterman, R. M., Weavil, J. C., Lewis, M. T., Layec, G., & Amann, M.
Affiliations
  • University of Utah (US)
  • Department of Medicine University of Utah Salt Lake City UT USA
Corresponding author
Hureau, Thomas J.
ORCID
Venue
The Journal of Physiology
Publisher
Wiley
Published
2022-06-02
Volume
600
Issue
13
Pages
3069-3081
ISSN
  • 0022-3751 (ISSN-L)
  • 1469-7793
DOI
10.1113/jp283036
PMC
PMC9250628
OpenAlex
W4281256727
Cited by
100
References
51
Citations by year
2026: 24 · 2025: 25 · 2024: 23 · 2023: 14 · 2022: 13
FWCI
19.60
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • The Journal of Physiology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
Clinical Science Research and Development (IK2CX002114)
Topics
  • Health Sciences › Medicine › Complementary and alternative medicine › Cardiovascular and exercise physiology
  • Physical Sciences › Engineering › Biomedical Engineering › Muscle activation and electromyography studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
Keywords
muscle acidosis, inorganic phosphate, central fatigue, peripheral fatigue, 31P NMR, voluntary activation, knee extension exercise, muscle afferents, intermittent exercise, neuromuscular function, skeletal muscle metabolism
MeSH terms
Acidosis, Electromyography, Fatigue, Humans, Male, Muscle Contraction, Phosphates, Phosphorus, Muscle, Skeletal, Muscle Fatigue

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