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 (31P‐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. 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 (31P‐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.

This study finds no change in neonatal T(4) levels despite maternal consumption of drinking water that contains perchlorate at levels in excess of the Environmental Protection Agency (EPA) drinking water equivalent level (24.5 microg/L) based on the National Research Council reference dose (RfD) [0.7 microg/(kg.day)]. Therefore the perchlorate RfD is likely to be protective of thyroid function in neonates of mothers with adequate iodide intake.

The impact of COVID-19 has been largely described after symptom development. Although the SARS-CoV-2 virus elevates heart rate (HR) prior to symptom onset, whether this virus evokes other presymptomatic alterations is unknown. This Case Study details the presymptomatic impact of COVID-19 on vascular and skeletal muscle function in a young woman (24yrs, 173.5cm, 89kg, BMI: 29.6kg·m-2). Vascular and skeletal muscle function were assessed as part of a separate study with the first and second visits separated by 2 weeks. On the evening following the second visit, the participant developed a fever and a rapid antigen test confirmed a positive COVID-19 diagnosis. Compared to the first visit, the participant presented with a markedly elevated HR (~ 30 bpm) and lower mean blood pressure (~8 mmHg) at the second visit. Vascular function measured by brachial artery flow-mediated dilation, reactive hyperemia, and passive leg movement were all noticeably attenuated (25-65%) as was leg blood flow during knee extension exercise. Muscle strength was diminished as was ADP stimulated respiration (30%), assessed in vitro, while there was a 25% increase in the apparent Km. Lastly, an elevation in IL-10 was observed prior to symptom onset. Notably, 2.5 months after diagnosis symptoms of fatigue and cough were still present. Together, these findings provide unique insight into the physiological responses immediately prior to COVID-19 symptom onset; they suggest that SARS-CoV-2 negatively impacts vascular and skeletal muscle function prior to the onset of common symptoms and may set the stage for the widespread sequelae observed following COVID-19 diagnosis.