Research Article

Elevated plasma lactate levels via exogenous lactate infusion do not alter resistance exercise-induced signaling or protein synthesis in human skeletal muscle

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Lactate has been implicated as a potential signaling molecule. In myotubes, lactate incubation increases mechanistic target of rapamycin complex 1 (mTORC1)- and ERK-signaling and induces hypertrophy, indicating that lactate could be a mediator of muscle adaptations to resistance exercise. However, the potential signaling properties of lactate, at rest or with exercise, have not been explored in human tissue. In a crossover design study, 8 men and 8 women performed one-legged resistance exercise while receiving venous infusion of saline or sodium lactate. Blood was sampled repeatedly, and muscle biopsies were collected at rest and at 0, 90, and 180 min and 24 h after exercise. The primary outcomes examined were intracellular signaling, fractional protein synthesis rate (FSR), and blood/muscle levels of lactate and pH. Postexercise blood lactate concentrations were 130% higher in the Lactate trial (3.0 vs. 7.0 mmol/L, P < 0.001), whereas muscle levels were only marginally higher (27 vs. 32 mmol/kg dry wt, P = 0.003) compared with the Saline trial. Postexercise blood pH was higher in the Lactate trial (7.34 vs. 7.44, P < 0.001), with no differences in intramuscular pH. Exercise increased the phosphorylation of mTORS2448 (∼40%), S6K1T389 (∼3-fold), and p44T202/T204 (∼80%) during recovery, without any differences between trials. FSR over the 24-h recovery period did not differ between the Saline (0.067%/h) and Lactate (0.062%/h) trials. This study does not support the hypothesis that blood lactate levels can modulate anabolic signaling in contracted human muscle. Further in vivo research investigating the impact of exercised versus rested muscle and the role of intramuscular lactate is needed to elucidate its potential signaling properties.


Resistance exercise is one of the primary stimulators of muscle protein synthesis and, in the long term, skeletal muscle accretion (31), which is a vital aspect of metabolic health and locomotor capacity (32). At the mechanistic level, evidence suggests that loading-induced increases in muscle protein synthesis and skeletal muscle mass are to a large extent mechanistic target of rapamycin complex 1 (mTORC1)-dependent (17).

Although the pivotal role of mTORC1 activation in resistance exercise-induced protein synthesis has been well established (5, 17), the precise molecular events that lead to the activation of mTORC1 and protein synthesis after resistance exercise require further elucidation. One theory relates to mechanotransduction, in which tension at the cell membrane caused by high-loaded muscle contractions leads to the synthesis of a glycerophospholipid, phosphatidic acid, which can directly activate mTOR at the lysosome (25). Moreover, a growing body of evidence indicates that low-load resistance exercise protocols that induce significant metabolic perturbations, such as repetitions performed to failure or the addition of blood flow occlusion, potently induce mTORC1 signaling, protein synthesis, and muscle growth (9, 14, 19, 29, 36, 43). Here it has been suggested that the substantially lower load is compensated by metabolite accumulation, either indirectly by increasing muscle fiber activation or directly through metabolite-induced cell signaling (12, 42). In this context, lactate is a metabolite of particularly exciting interest.

During the last few decades, we have come a long way from the view that lactate, the end product of glycolysis, is a fatigue-inducing waste product to recognizing lactate as an important metabolic substrate (7). Now, studies have begun to show that lactate has cell signaling properties in skeletal muscle and other tissues. As early as 1964, Green and Goldberg (18) illustrated that the incubation of fibroblasts with increasing levels of lactate stimulated collagen synthesis. Almost 40 yr later, that observation received mechanistic support in macrophages and wound models, in which lactate treatment was shown to stimulate vascular endothelial growth factor expression (11, 23, 47). Not much later, Liu et al. (30) identified the G protein coupled receptor 8 (GPR81) as a membrane-bound receptor for lactate in adipose tissue, which upon ligand binding reduces cAMP levels and inhibits lipolysis. Interestingly, GPR81 mRNA was also found to be expressed in human skeletal muscle.

With more specific regard to the potential signaling properties of lactate in skeletal muscle tissue, Hashimoto et al. (21) first showed that the incubation of L6 myotubes with 10 and 20 mM lactate stimulated the mRNA expression of monocarboxylate transporter 1 (MCT-1) and peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α). From the perspective of resistance exercise and muscle growth, Oishi et al. (39) illustrated that the treatment of C2C12 cells with 10 mM lactate stimulated mTORC1 signaling and myogenic activity. Subsequently, lactate treatment was shown to induce C2C12 myotube differentiation and hypertrophy and accelerate muscle generation in an in vivo muscle damage model (48). These data are also supported by the work of Ohno et al. (38), who illustrated that lactate could induce myotube size in an extracellular signal-regulated kinase (ERK)-dependent manner. Moreover, intraperitoneally injected lactate in mice, which resulted in peak blood lactate levels of 20 mM, was shown to rapidly stimulate mTORC1 and ERK signaling in the quadriceps muscle (10). Recently, daily oral lactate treatment in mice for 2 wk was also shown to increase muscle weight and fiber cross-sectional area of the tibialis anterior (37).

Taken together, emerging evidence from in vitro and rodent models suggests that lactate could act as a molecular trigger of anabolic signaling and growth of skeletal muscle fibers, indicating that lactate could be a mediator of muscle adaptations to resistance exercise. However, the potential signaling properties of lactate in human skeletal muscle, or any other human tissue in vivo, have (to our knowledge) never been studied. Accordingly, the aim of the present work was to investigate whether lactate could exhibit cell signaling properties in human skeletal muscle in combination with contractile activity. For this purpose, we established an experimental model in which resistance exercise was performed under the venous infusion of saline or sodium lactate to manipulate systemic levels of lactate during exercise. Our goal was to create a model where exercise-related factors (load, repetitions, time under tension) and systemic factors (myokines, cytokines, hormones) would be similar between situations, and to the largest extent possible, only differ with regard to the levels of lactate. Because the existing relatable in vivo data have only documented circulating levels of lactate, together with the fact that the only illustrated mechanism of direct lactate signaling is through an extracellular receptor, our main focus was to manipulate blood lactate levels. We hypothesized that a sodium lactate infusion would increase blood and muscle levels of lactate during exercise and augment resistance exercise-induced mTORC1 and ERK signaling and protein synthesis rates.



Sixteen young female and male subjects were recruited for participation in this study. To be eligible for enrollment in the study, the subjects were required to be free from medical conditions, injuries, drugs, and dietary supplements and to have performed resistance exercise involving the legs one to two times per week during at least the last 12 mo. All subjects were regarded as training-accustomed and performed four to seven training sessions per week involving both resistance and endurance exercises and some various team sport activities. The subject characteristics are presented in Table 1. After being fully informed of the purpose of the study and its associated risks, all subjects provided their written consent to participate. The study protocol was preapproved by the Regional Ethical Review Board in Stockholm and was performed in accordance with the principles outlined in the Declaration of Helsinki.

Table 1. Subject characteristics

Weight, kg69 ± 1161 ± 577 ± 8
Height, cm173 ± 10165 ± 5181 ± 5
1-RM left, kg88 ± 2171 ± 11104 ± 14
1-RM right, kg88 ± 2072 ± 9104 ± 14
Peak power, W/kg11 ± 1.99 ± 1.512 ± 1.0
Mean power, W/kg7 ± 1.36 ± 0.98 ± 0.6
Type II MHC distribution%60 ± 354 ± 467 ± 3
Leg volume left, cm37,590 ± 1,8206,430 ± 1,1608,750 ± 1,640
Leg volume right, cm37,660 ± 1,8506,500 ± 1,1508,830 ± 1,720
Leg muscle area left, cm2150 ± 27129 ± 14172 ± 18
Leg muscle area right, cm2151 ± 27130 ± 13172 ± 19

1-RM, maximal single leg knee-extensor strength test; MHC, myosin heavy chain.

General design.

To test the postulated hypothesis, a randomized, placebo-controlled crossover design was employed in which each subject performed two sessions of a unilateral leg extension resistance exercise with a simultaneous venous infusion of either sodium lactate (Lactate trial) or isotonic saline (Saline trial). These two experimental trials were separated by 7–10 days. The entire study consisted of three preliminary sessions and two experimental trials that were all completed within 5–6 wk. The subjects were instructed to maintain their habitual dietary intake and physical activity pattern throughout the entire experimental period, although during the 2 days before each trial, they were told to refrain from physical exercise. A schematic overview of the experimental design is provided in Fig. 1.

Fig. 1.

Fig. 1.Schematic overview of the trial design. Biopsy needles represent muscle biopsy time points. Syringes indicate venous blood sampling time points. The numbers below indicate the time (min) after beginning the infusion, the set number, and the length (min) of recovery, in that order. Res.Ex indicates knee-extensor resistance exercise. WU = three warm-up sets. The sodium lactate infusion rate was set to 50 µmol·kg−1·min−1 with the saline infusion having an equivalent volume. After 180 min of recovery, the subjects were fed a standardized meal (34 g protein, 21 g carbohydrate, and 7 g fat), after which they left the laboratory and returned in an overnight fasted state the next morning for 24-h sampling.


All subjects visited the laboratory three times for preliminary testing. During the first visit, the subjects went through a health screening, had their leg volume and muscle area determined, performed a maximal single leg knee-extensor strength test (1-RM) for both legs, and performed a 30-s all-out cycling sprint to estimate anaerobic capacity. Leg volume was calculated according to the method of Tothill and Stewart (46), and bone-free leg muscle area was calculated according to Knapik et al. (28). The participants’ thigh length was measured from the trochanter major to the lateral femur epicondyle; three circumferences were measured at the upper fourth, mid-half, and lower three-quarters of the thigh length; skinfold was measured at mid-thigh; and the epicondyle diameter of the femur was assessed. These measurements served as data for the leg volume and leg muscle area calculations.

The 1-RM testing was performed for each leg separately using a leg extension machine (Star Trac, Vancouver, WA) according to known principals. Following a brief warm-up, the load was gradually increased after each lift until the subject could no longer perform a single repetition (90–180° knee angle). The nondominant leg initiated the test, and this was subsequently alternated between each attempt, with 5 min of rest between lifts for each leg. The subjects’ 1-RM correlated well with their leg volume (R = 0.87) and leg muscle area (R = 0.89). Following 15 min of rest, the 30-s all-out cycling sprint was performed on an electronically braked cycle ergometer (SRM Ergometer, Schoberer Rad Messtechnich, Jülich, Germany). After 5 min of cycling at 100 W, a maximal 30-s cycling effort was performed at a fixed cadence of 115 rpm, with the participants being heavily encouraged by the test leaders during the sprint. The power output was sampled every 0.5 s to determine the peak power and mean power over 30 s.

The second and third visits served as familiarization sessions in which the subjects performed the exercise protocol (see below) that would be used during the experimental trials. During these sessions, the desired contraction speed was practiced and, if applicable, the load was adjusted to meet the set criteria of the protocol. These sessions were scheduled 1 wk apart with the final familiarization session being performed 7–10 days before the first trial.

Experimental trials.

On the day before the first trials and ∼12 h before initiation, the subjects orally ingested 3.5 mL of 70% deuterium oxide/kg body wt (Cambridge Isotope Laboratories, Tewksbury, MA) to determine the rate of muscle protein synthesis. Prior to the second trial, the subjects ingested 0.15 mL of 70% deuterium oxide/kg body wt per day between trials to reach the same level of isotope enrichment as in the first trial. All doses were taken as ∼50 mL boluses separated by at least 30 min to avoid the known side effects of vertigo and nausea.

On the days of the trials, the subjects reported to the laboratory at 07:00 AM after fasting since 10:00 PM the evening before. Upon arrival, the subjects were instructed to take a supine position and had a 19-gauge Teflon catheter inserted into the antecubital vein of each arm; one was used for repeated blood sampling and the other was used for infusion. Thereafter, a baseline blood sample was drawn to ensure proper blood status to safely proceed with the trials. Immediately after collection, whole blood was analyzed for levels of sodium, potassium, hemoglobin, hematocrit, pH, and base excess using the i-STAT1 handheld blood analyzer together with EG6+ cassettes (Abbot Laboratories, Chicago, IL). Blood levels of lactate and glucose were determined with an automatic analyzer (Biosen C-line, EKF-Diagnostics, Cardiff, UK). Thereafter, an initial baseline biopsy was taken from the vastus lateralis muscle of the leg randomized for exercise that trial.

After we completed the baseline sampling, a venous infusion of sodium lactate (APL, Stockholm, Sweden) or a volume-matched isotonic saline infusion (Fresenius Kabi AB, Uppsala, Sweden) was initiated with the subjects in a supine position. The sodium lactate solution had a concentration of 1 M, pH 6.4, and was delivered at an infusion rate of 50 µmol·kg−1·min−1. Following 20 min of baseline infusion, the subjects were moved to the leg extension machine and initiated the exercise protocol. Exercise was performed on one leg, starting with three warm-up sets with 10 repetitions at 0, 25, and 50% of their individual 1-RM, followed by six sets at 75% of their 1-RM, during which the load was gradually decreased if necessary to ensure that at least 8 but not more than 10 repetitions were completed at fatigue. The warm-up sets were separated by 2 min of rest, and the working sets were separated by 3 min. The individual load, number of repetitions, and time under tension were matched between the two trials. After the last warm-up set, the second set, and the fourth set, a bolus injection of 0.1 mL/kg body wt of sodium lactate or saline was administered through the venous catheter. In total, the subjects were given 216 ± 8 mL of sodium lactate or saline.

After completion of the final set, the infusion was terminated, and the subjects were rapidly moved to a supine position for a second muscle biopsy that was taken 60–120 s after the last contraction. The subjects then remained in a supine position for 3 h, during which additional muscle biopsies were collected at 90 and 180 min. Blood samples were drawn 10 and 20 min after the baseline infusion; after the warm-up, second, fourth, and final sets of exercise; and after 10, 20, 30, 45, 60, 90, 120, and 180 min of recovery. Whole blood samples were analyzed directly as described above with the remaining blood collected into heparinized tubes. For subject safety, all samples were analyzed for pH, base excess, sodium, and potassium in the Lactate trial, whereas these parameters were only determined at rest, midexercise, postexercise, and at 30, 60, 90, and 180 min of recovery in the Saline trial. When the 3-h recovery period was completed, the subjects were given a whey protein drink and an energy bar (Enervit, Milan, Italy), which together provided them with 34 g of protein, 21 g of carbohydrate, and 7 g of fat. The subjects then left the laboratory and were instructed to refrain from all types of exercise and intense physical activities, keep a standardized diet, and then return to the laboratory in the fasted state the following morning for a 24-h muscle biopsy and blood sample. The next trial was performed 7–10 days later with the infusion and leg used for exercise and biopsies randomized in a counter-balanced manner.

Muscle biopsies were taken using a Bergström needle (Stille, Torshälla, Sweden) with applied suction under local anesthesia. The first biopsy was taken ∼15 cm above the patellae, with the subsequent samples all obtained from a new incision ∼2 cm proximal to the previous one. The tissue samples were immediately blotted free of blood and rapidly frozen in liquid nitrogen for storage at −80°C until further processing. To assess whether the subjects felt the infusion with sodium lactate, visual analog scale (VAS) ratings for discomfort/pain were employed. This was a standard 100-mm VAS ranging from “no pain/discomfort” to “worst imaginable pain/discomfort”, thereby yielding a score between 0 and 100. After the 20-min basal infusion and after the second and fifth sets of exercise, the subjects were asked to rate their feelings of discomfort/pain in the exercised leg and somatically according to the VAS. Additionally, when the experimental trials were complete, the subjects were asked whether they could tell or guess in which trial they had received sodium lactate.

Plasma analysis.

Blood samples collected in heparinized tubes were kept on ice until centrifugation at 3,000 rpm for 10 min to obtain plasma samples that were subsequently stored at −80°C. Plasma lactate concentrations were analyzed spectrophotometrically as described by Bergmeyer (4) on a 96-well plate reader (Infinite 200 Pro, Tecan, Männedorf, Switzerland).

Muscle tissue processing.

The muscle samples were lyophilized and thoroughly dissected free from blood and connective tissue under a light microscope (Carl Zeiss, Germany), leaving only very small fiber bundles intact. The fiber bundles were then carefully mixed and split into homogenous aliquots for each subsequent analysis.

Muscle lactate and pH.

Muscle levels of lactate were determined in the TCA extracts from 2 mg of lyophilized muscle after neutralizing the sample with 1 M KOH. Lactate levels in the extracts were subsequently determined spectrophotometrically as described by Bergmeyer (4) on a 96-well plate reader (Infinite 200 Pro, Tecan, Switzerland). Analyzed muscle lactate levels in mmol/kg dry muscle were also recalculated to mmol/L intracellular (i.c.) water according to the data of Sjøgaard et al. (43a). Muscle pH was determined according to the method of Sahlin et al. (40a) but with a few modifications. In brief, 2 mg of lyophilized muscle was homogenized in a nonbuffering solution containing 145 mM potassium chloride, 10 mM sodium chloride, and 5 mM sodium fluoride using a Bullet Blender (Next Advance, NY) at 4°C for 2 min. The homogenates were then rapidly placed in a 38°C heating block, and pH was measured in duplicate readings with an ultra-microelectrode linked to a Seven2Go pH meter (Mettler Toledo, Greifensee, Switzerland).


To assess protein signaling, 3.5 mg of lyophilized muscle was homogenized in ice-cold buffer (100 µL/mg dry wt) consisting of 2 mM HEPES (pH 7.4), 1 mM EDTA, 5 mM EGTA, 10 mM MgCl2, 50 mM β-glycerophosphate, 1% TritonX-100, 1 mM Na3VO4, 2 mM dithiothreitol, 1% phosphatase inhibitor cocktail (Sigma P-2850), and 1% (vol/vol) Halt Protease Inhibitor Cocktail (Thermo Scientific, Rockford, IL) using a BulletBlender (NextAdvance, Troy, NY). The homogenates obtained were rotated for 30 min at 4°C and subsequently centrifuged at 10,000 g for 10 min at 4°C. The resulting supernatant was collected for immunoblotting and the pellet further processed for myosin heavy chain composition (see Myosin heavy chain composition). Protein concentration was determined in an aliquot of the supernatant using the Pierce 660 nm protein assay (Thermo Scientific). The samples were diluted in 4× Laemmli sample buffer (Bio-Rad Laboratories, Richmond, CA) and homogenizing buffer to obtain a final protein concentration of 1.5 µg/µL. The samples were then heated at 95°C for 5 min to denature the proteins. The samples were stored at −20°C until separation on SDS-PAGE.

For protein separation, 22.5 µg of protein from each sample was loaded on 26-well Criterion TGX gradient gels (4–20% acrylamide; Bio-Rad Laboratories), with all samples from each subject loaded onto the same gel, and electrophoresis was performed on ice at 300 V for 30 min. Next, the gels were equilibrated in transfer buffer (25 mM Tris base, 192 mM glycine, and 10% methanol) for 30 min at 4°C, after which the proteins were transferred to polyvinylidene fluoride membranes (Bio-Rad Laboratories) at a constant current of 300 mA for 3 h at 4°C. Equal loading and transfer were then confirmed by staining the membranes with MemCode Reversible Protein Stain Kit (ThermoFisher Scientific) (1).

Following destaining, the membranes were blocked for 1 h at room temperature in Tris-buffered saline (TBS; 20 mM Tris base, 137 mM NaCl, pH 7.6) containing 5% nonfat dry milk and then incubated overnight with commercially available primary antibodies diluted in TBS supplemented with 0.1% Tween-20 containing 2.5% nonfat dry milk (TBS-TM). The following morning, the membranes were washed with TBS-TM and incubated for 1 h at room temperature with secondary antibodies conjugated with horseradish peroxidase. Next, the membranes were washed with TBS-TM (2 × 1 min, 3 × 10 min), followed by 4 × 5 min with TBS. Finally, the proteins were visualized by applying SuperSignal West Femto Chemiluminescent Substrate (ThermoFisher Scientific) to the membranes, followed by detection in the molecular imager ChemiDoc MP and quantification of the detected bands using the Image Laboratory software (Bio-Rad Laboratories). Prior to blocking, the membranes from each gel were cut into stripes for each target protein and then assembled. Thus, all membranes with samples from one subject were exposed to the same blotting conditions. Following visualization, the membranes were stripped of the phospho-specific antibodies, using Restore Western Blot Stripping Buffer (ThermoFisher Scientific) for 30 min at 37°C, after which the membranes were washed and reprobed with primary antibodies for each respective total protein as described above. All phospho-proteins were normalized to their corresponding total protein.


For the immunoblotting analysis, primary antibodies against ribosomal protein S6 kinase 1 (S6K1; Thr389, no. 9234; total no. 2708), mTOR (Ser2448, no. 2971; total, no. 2983), S6 (Ser240/244, no. 2215; total, no. 2317), 40-kDa proline-rich Akt substrate (PRAS40; Thr246, no. 2997; total, no. 2691), tuberous sclerosis complex 2 (TSC2; Thr1387, no. 5584; total, no. 3635), eukaryotic initiation factor 4E-binding protein 1 (4E-BP1; Ser65, no. 9456; total, no. 9644), eukaryotic elongation factor 2 (eEF2; Thr56, no. 2331; total, no. 2332), AMP-activated protein kinase (AMPK; Thr172, no. 4188; total, no. 2532), and p44 or ERK (Thr202Tyr204, no. 9101; total, no. 9102) were purchased from Cell Signaling Technology (Beverly, MA). Primary antibodies for 4E-BP1 Thr46 (no. sc-18090R) were purchased from Santa Cruz Biotechnology (Heidelberg, Germany).

All primary antibodies were diluted 1:1,000 except for phospho-eEF2, total eEF2, and total 4E-BP1, which were diluted 1:2,000, and 4E-BP1 Thr46, which was diluted 1:200. Secondary anti-rabbit (1:10,000; no. 7074) and secondary anti-mouse (1:10,000; no. 7076) antibodies were purchased from Cell Signaling Technology.

Myosin heavy chain composition.

The myosin heavy chain composition was analyzed in all the biopsies of each subject using the myofibrillar pellet that was collected when preparing the samples for immunoblotting (see above). Following serial washing, the protein concentration of the myofibrillar pellet was determined after being dissolved in 200 µL of homogenization buffer. The samples were then prepared for SDS-PAGE in 2× Laemmli sample buffer, and 0.5 µg of protein was loaded for each sample onto a 4% stacking, 6% resolving polyacrylamide gel. Electrophoresis was then performed at 100 V for ∼18 h at 4°C. The myosin heavy chain (MHC) bands were subsequently visualized using a silver staining kit (ThermoFisher Scientific, MA), and MHC type I and type II were quantified using densitometry (intensity × mm2) and expressed as the percentage of the total amount of I + II in each biopsy.

Muscle protein fractional synthetic rate.

To determine mixed muscle protein fractional synthetic rate (FSR), analysis of intracellular free levels and muscle protein-bound levels of 2H-alanine was performed. Approximately 3.5 mg of lyophilized muscle tissue was pelleted and extracted twice with 2% perchloric acid using a glass rod. To determine the intracellular enrichment of free 2H-alanine, the two extracts from the mixed muscle samples were combined and further analyzed using LC-MS/MS as described by Bornø and van Hall (6). The remaining pellet was washed twice with 70% ethanol, hydrolyzed overnight in 6 M HCl at 110°C, dissolved in 50% acetic acid, and then passed through a cation exchange column. To determine the enrichment of protein-bound 2H-alanine, amino acids derived from the purified pellet were converted to their N-acetyl-N-propyl esters and analyzed by gas chromatography–pyrolysis–isotope ratio mass spectrometry (GC-P-IRMS; Delta V, ThermoFisher Scientific, Bremen, Germany).

The protein fractional synthesis rate was determined using the precursor–product approach: FSR = ΔEp/(Eic × t) × 100, in which ΔEp is the difference in protein-bound 2H-alanine enrichment between biopsies taken at rest and after 24 h of recovery, Eic is the average intracellular free 2H-alanine enrichment in the two biopsies, and t is the time between biopsies in hours multiplied by 100 to express FSR as the percentage per hour (%/h).

Statistical analyses.

The data were analyzed using TIBCO Statistica 13 for Windows (TIBCO Software Inc., Palo Alto, CA). The data are presented as the means ± standard deviation (SD) unless otherwise noted. The normality of the variables was assessed with histograms and the Shapiro–Wilk test of normality before the analyses were executed. All data were deemed acceptable for parametric statistical tests. A two-way repeated measures analysis of variance (ANOVA) trial × time was used for the data analyses on blood lactate, glucose, and plasma lactate (2 × 15); potassium, sodium, base excess and blood pH (2 × 7); muscle lactate (2 × 3); and hemoglobin and muscle pH (2 × 2). Fisher’s least significant difference post hoc test was performed for any of these analyses if significant main effects or interaction effects appeared. We also evaluated whether differences in the aforementioned variables occurred in response to the sodium lactate infusion in a sex-specific analysis. The subjects were separated into male and female groups, and a dual two-way repeated measures ANOVA was performed while the same post hoc test was performed for the entire group if significant main effects or interaction effects appeared. To evaluate the effects on muscle protein synthesis rates over 24 h, a Student’s paired t test was performed. Data were considered statistically significant if P < 0.05. The data that support the findings of this study are available from the corresponding author upon reasonable request.


Trial performance.

All subjects except for one performed the exact same number of repetitions at matching loads during both trials. During the sodium lactate infusion trial, one subject had to reduce the load by 2.5 kg during the second to sixth sets and perform one less repetition per set to properly execute the protocol. Time under tension did not differ between the two trials (P = 0.94). VAS ratings did not differ between trials, with the highest scores being 15 ± 16 and 11 ± 16 for the somatic rating and 15 ± 15 and 17 ± 19 for the leg rating in the Saline and Lactate trials, respectively. No subjects could identify in which trial they received the lactate infusion, but nine subjects guessed correctly and seven guessed incorrectly. The last sodium lactate bolus after the fourth set was omitted for one subject because that subject complained of nausea and already had blood lactate levels over 10 mmol/L. All 160 muscle and 512 blood samples were successfully collected, but at two occasions late in the recovery period in each trial, the i-STAT malfunctioned, leading to four missing data points for the blood data.

Blood parameters.

Resistance exercise induced an increase in blood lactate levels that peaked at 3.0 ± 0.7 mmol/L postexercise (P < 0.001 for time; Fig. 2A) and returned to baseline after 60 min of recovery in the Saline trial. The peak level was 2.7 ± 0.6 mmol/L in the women and 3.3 ± 0.7 mmol/L in the men. The sodium lactate infusion resulted in ∼130% greater blood lactate levels with a peak of 6.8 ± 1.3 mmol/L postexercise; additionally, lactate levels were higher than those at baseline and in the Saline trial until 90 min of recovery (P < 0.001 for time and trial interaction; Fig. 2A). Here, the peak level was 7.0 ± 1.5 mmol/L for women and 6.5 ± 1.2 mmol/L for men. Plasma lactate levels mirrored the blood lactate levels but peaked at 4.4 ± 0.9 mmol/L in the Saline trial and 8.8 ± 1.6 mmol/L in the Lactate trial immediately postexercise (P < 0.001 for time and trial interaction; Fig. 2B). Plasma lactate levels were ∼90% greater than mean blood levels at baseline, but plasma lactate levels were only 30% higher compared with blood lactate levels during the peak in the Lactate trial.

Fig. 2.

Fig. 2.Blood (A) and plasma (B) levels of lactate, blood pH (C), blood base excess (D), and blood levels of sodium (E) and potassium (F) in samples taken at rest before infusion, during infusion/exercise, and recovery. Hemoglobin content (G) and hematocrit (H) in blood samples taken before (Pre) and after exercise (Post). All data presented are the means ± SD (n = 16 subjects). *P < 0.05 vs. baseline, #P < 0.05 vs. Saline trial.

In the Saline trial, blood pH was slightly reduced from 7.35 ± 0.03 to 7.34 ± 0.02 postexercise but then increased compared with baseline during recovery, resulting in a pH of 7.38 ± 0.02 at 180 min postexercise (P < 0.001 for time; Fig. 2C). The sodium lactate infusion had a distinct alkalizing effect in blood with a pH of 7.44 ± 0.02 noted directly after exercise; this increase was greater than that reported at rest and in the Saline trial throughout the entire 180-min recovery period (P < 0.001 for time and trial interaction). The blood base excess followed the changes in blood pH (Fig. 2D). In the Saline trial, the base excess was reduced from 1.7 ± 2.1 mmol/L at rest to −0.6 ± 2.4 postexercise, which then was reversed during recovery (P < 0.001 for time). In the Lactate trial, the base excess started at the same level and increased to 4.1 ± 3.5 mmol/L after exercise, reaching 6.9 ± 3.1 mmol/L after 180 min of recovery (P < 0.001 for time). Irrespective of trial and time, men displayed 2–3 mmol/L higher base excess compared with the women.

As expected, sodium levels in the blood increased after infusion in the Lactate trial, with levels reaching 143 ± 1.6 mmol/L after exercise compared with 140 ± 1.0 mmol/L at rest (Fig. 2E). In the Saline trial, sodium levels also increased from rest to 142 ± 1.2 mmol/L after exercise; however, blood sodium levels were higher after the sodium lactate infusion throughout the entire trial (P < 0.001 for time and trial interaction). Blood potassium levels increased with exercise by 10% and 5% in the Saline and Lactate trials, respectively (P < 0.001 for time and trial interaction; Fig. 2F). During recovery, blood potassium levels decreased below baseline levels in the Lactate trial, whereas the mean potassium levels were 11% higher in the Saline trial throughout the entire recovery period. In the Saline trial, hemoglobin levels and hematocrit increased immediately after exercise by 5.8% and 6.1%, respectively, whereas no change was noted in the Lactate trial (both P < 0.001 for time and trial interaction, Fig. 2, G and H).

Muscle lactate and pH.

With regard to muscle lactate levels, the statistical analysis revealed a main effect of time (P < 0.001) and a main effect of trial (P = 0.003), with levels being ∼20% higher in the Lactate trial than in the Saline trial (32 vs. 27 mmol/kg dry wt or 7.25 vs. 6.20 mmol/L i.c. water) immediately postexercise (Fig. 3A). In the Saline trial, muscle lactate levels postexercise were 22 ± 8 mmol/kg dry wt in the women and 32 ± 15 mmol/kg dry wt in the men (5.0 and 7.25 mmol/L i.c. water, respectively), whereas the corresponding values in the Lactate trial were 27 ± 6 and 37 ± 13 mmol/kg dry wt (6.1 and 8.4 mmol/L i.c. water), respectively. There were no differences between trials with regard to basal or exercise-induced changes in muscle pH. In the Saline trial, muscle pH was reduced from 7.29 ± 0.04 at rest to 7.22 ± 0.07 postexercise, whereas the corresponding values in the Lactate trial were 7.28 ± 0.05 and 7.23 ± 0.07, respectively (P = 0.001 for time; Fig. 3B). There was a strong correlation between muscle lactate levels and muscle pH in the Saline trial (r = 0.84, P < 0.001; Fig. 3C); this correlation was also noted in the Lactate trial but with a slightly lower correlation coefficient (r = 0.74, P < 0.001; Fig. 3D).

Fig. 3.

Fig. 3.Muscle levels of lactate in muscle samples taken at rest before infusion (Pre), immediately after the exercise (Post), and after 90 min of recovery (A) and muscle pH at rest and immediately after exercise (B). All data presented are the means ± SD (n = 16 subjects). *P < 0.05 vs. baseline, #P < 0.05 vs. Saline trial. Correlation between muscle levels of lactate and muscle pH in the Saline trial (C) and the Lactate trial (D). The correlations include data from samples taken at rest and immediately after exercise for 16 subjects; thus, each panel includes 32 data points.

Protein signaling.

The sodium lactate infusion did not modulate the response for any of the signaling proteins analyzed. Accordingly, all changes presented in this section are effects of exercise (time), and the lack of a treatment effect will not be repeated continuously in the description of the results.

Resistance exercise stimulated an increased phosphorylation of S6K1T389, with the highest increase above rest (∼4-fold) being noted at 180 min of recovery, independent of the trial (P < 0.001; Fig. 4A). Interestingly, a 119–125% higher S6K1T389 phosphorylation compared with before exercise was noted at 24 h of recovery in both trials (P = 0.02). The changes in S6K1T389 on the group level were also displayed by the women and men separately, with the exception that the women did not exhibit significantly elevated phosphorylation at 24 h. Robust effects of exercise were also noted for S6S235/236 phosphorylation, with 6- to 12-fold increases above rest during the 180-min recovery period (P < 0.001) and 5- to 6-fold higher levels at 24 h of recovery (P = 0.007, data not shown). Immediately after exercise, the phosphorylation of mTORS2448 increased by 40–45% in both trials and remained elevated above resting values at 180 min of recovery (P < 0.001) but returned to baseline values at 24 h of recovery (Fig. 4B). For the women, increases in mTORS2448 phosphorylation were only present immediately after exercise, whereas the men exhibited an elevated degree of phosphorylation at all time points of the 180-min recovery period. The phosphorylation of 4E-BP1T46 was reduced by ∼50% after exercise in both trials (P < 0.001), returned to baseline values at 90 min of recovery, and was elevated by 31–34% above baseline at 180 min (P < 0.001, Fig. 4C). The Ser65 residue of 4E-BP1 was also dephosphorylated by ∼50% in both trials postexercise (P < 0.001) and remained reduced by ∼30% compared with baseline values at 90 min of recovery (P = 0.006). At 180 min of recovery, 4E-BP1S65 had returned to baseline values, and at 24 h of recovery, it was increased by ∼30–50% compared with baseline values in both trials (P < 0.001, Fig. 4D). Whole group effects on both 4E-BP1 phosphorylation sites were followed very closely when evaluating changes separately in women and men.

Fig. 4.

Fig. 4.Phosphorylation of ribosomal protein S6 kinase 1 (S6K1) at Thr389 (A), mechanistic target of rapamycin (mTOR) at Ser2448 (B), phosphorylated eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) at Thr46 (C), 4E-BP1 at Ser65 (D), eukaryotic elongation factor 2 (eEF2) at Thr56 (E), AMP-activated protein kinase (AMPK) at Thr172 (F), 40-kDa proline-rich Akt substrate (PRAS40) at Thr246 (G), and p44 at Thr202/Tyr204 (H) at baseline (Pre), immediately after exercise (Post) and following 90 or 180 min or 24 h of recovery. Data presented in the bars are the means ± SD (n = 16 subjects). White bars represent the Saline trial and black bars represent the Lactate trial. *P < 0.05 vs. baseline.

The phosphorylation of eEF2Thr56 increased by 25–29% immediately after exercise and was subsequently reduced by 37–49% below baseline values at 90 and 180 min of recovery (P < 0.001, Fig. 4E). At 24 h of recovery, eEF2Thr56 phosphorylation remained 17–28% lower than at preexercise (P = 0.008). The women did not exhibit any increased phosphorylation of eEF2Thr56 immediately after exercise, but a significant reduction was exhibited at 90 min, 180 min, and 24 h of recovery. By contrast, the men displayed an ∼50% increase immediately after exercise but no significant reduction at 24 h of recovery. There was a small (∼25%) but significant increase in AMPKThr172 phosphorylation after exercise (P = 0.01, Fig. 4F), which subsequently returned to baseline values at 90 min of recovery and then remained unchanged throughout the duration of the trial. In the sex-specific analysis, only the women exhibited increased AMPKThr172 phosphorylation after exercise. Postexercise phosphorylation of PRAS40Thr246 was reduced by 36–38% compared with preexercise levels, whereas at 90 and 180 min of recovery, the phosphorylation had increased by ∼30% and ∼15% compared with initial levels, respectively (P < 0.001, Fig. 4G). Group-level effects on PRAS40Thr246 phosphorylation were also evident when women and men were analyzed separately, except for the 180-min increase, which did not reach statistical significance. The phosphorylation of p44Thr202/Tyr204 was increased by 72–90% in the postexercise biopsy (P = 0.04, Fig. 4H) but returned to and remained at baseline levels after 90 min of recovery. The postexercise increase in p44Thr202/Tyr204 phosphorylation was only detected in women when performing the sex-specific statistical analysis (Fig. 5).

Muscle protein synthesis.

The intracellular enrichment of 2H-alanine, which acts as a precursor pool for protein synthesis, did not differ between trials. In the Saline and Lactate trials, the intracellular enrichment at baseline was 0.012 ± 0.0023 and 0.012 ± 0.0019, which decreased to 0.011 ± 0.0023 and 0.011 ± 0.0017 after 24 h of recovery (P = 0.005, data not shown), respectively. The FSR over 24 h of exercise and recovery was 0.067 ± 0.026%/h in the Saline trial and 0.062 ± 0.017%/h in the Lactate trial; these rates were not significantly different (Fig. 6). Moreover, the average FSR for both trials did not differ between the women (0.065 ± 0.027%/h) and men (0.064 ± 0.017%/h).

Fig. 5.

Fig. 5.Representative Western blots for the proteins presented in Fig. 4.

Fig. 6.

Fig. 6.Mixed muscle protein fractional synthetic rate (FSR) during 24 h of exercise and recovery in the Saline trial and Lactate trial. ●, an individual subject (n = 16).


In the present study, we aimed to investigate the potential role of lactate as a signaling molecule in human skeletal muscle. For this we used a novel in vivo experimental model, in which male and female subjects performed resistance exercise with a venous infusion of sodium lactate or saline, together with sampling of multiple muscle biopsies. The lactate infusion, which was not sensed by the subjects or shown to alter exercise performance, resulted in 130% higher blood lactate levels and 20% higher muscle lactate levels of lactate compared with saline infusion. However, significantly elevated systemic levels of lactate did not modulate mTORC1 or ERK signaling in human skeletal muscle in relation to contractile activity, which was in contrast to our hypothesis and what has been indicated in previous in vitro and rodent models. In our view, there are four apparent potential explanations for the lack of effect from the lactate treatment: 1) the acquired blood lactate levels were insufficient to stimulate a direct signaling response; 2) intramuscular lactate levels are key for the stimulation of a signaling response, and in this study, differences in muscle lactate levels were only minor; 3) the large effect of muscle contractions on anabolic signaling may override the potentially smaller anabolic signaling properties of lactate illustrated in resting muscle cells; and 4) lactate does not possess anabolic signaling properties in human skeletal muscle.

As expected, resistance exercise induced a clear stimulation of both mTORC1 and ERK signaling (2, 41), but this response was not modulated by markedly elevated blood lactate levels. To date, the only illustrated mechanism by which lactate could exert direct signaling properties is through the cell surface-located GPR81 (30). Data from Ohno et al. (38) clearly suggested that lactate-induced ERK signaling in C2C12 cells was dependent on GPR81 activation. This suggests that the lactate levels in blood are key for stimulating a signaling response and that the lack of significant effects in the present study could be explained by the somewhat lower blood lactate levels attained in the Lactate trial as compared with previous studies. Although the 7-mM blood lactate levels (9 mM in plasma) noticed in the Lactate trial were substantially greater than those in the Saline trial as well as fully physiologically relevant for resistance exercise, they were still lower than the 10 mM used in previous in vitro studies to stimulate significant responses (21, 39, 48); however, those studies did not assess lower levels.

We set out to attain blood lactate levels of ∼10 mM while keeping endogenous production as low as possible and still loading the muscle properly, but this proved quite challenging. When we employed a high-load, low-volume exercise protocol, endogenous production was low while lactate clearance was high, which limited accumulation. Conversely, a high exercise volume with high endogenous lactate production could have limited between-trial differences. On the other hand, a markedly elevated sodium lactate infusion rate would have resulted in substantial blood alkalosis (>pH 7.45), thereby reducing physiological relevance. Sodium lactate infusions have previously been employed at resting conditions or during low- to moderate-intensity steady-state cycling (3335, 51), but to our knowledge, they have never been employed in combination with intermittent or anaerobic exercise. In those studies, with infusion rates ranging from 32–50 µmol·kg−1·min−1 over 90 min at states of rest or with cycling exercise at 75% of maximal oxygen consumption (V̇o2max), blood lactate levels of 3.8–6.9 mM were obtained. Notably, these studies sampled forearm arterial or arterialized blood, which has been shown to have higher lactate concentrations than forearm venous blood following sodium lactate infusion at rest (8). Because we were unable to sample blood from an artery, we can only speculate as to what lactate levels the vastus lateralis was exposed. Nonetheless, the 7-mM lactate concentration measured in forearm venous blood in the present study suggests that our model was successful in substantially increasing blood lactate during exercise with previous studies in mind.

Although there were major differences in blood lactate levels between trials, muscle lactate levels were only marginally higher in the Lactate trial (∼6.20 vs. ∼7.25 mmol/L i.c. water postexercise). To assess muscle-to-circulatory exchange, these muscle lactate levels must be considered in relation to the postexercise plasma levels (4.4 mM in the Saline trial and 8.9 mM in the Lactate trial) with the assumption of free interstitial-to-plasma exchange. Accordingly, there was a smaller gradient between blood and muscle in the Lactate trial. Thus, although lactate uptake by the muscle would be expected in this situation, based on previous work on resting and contracting muscle (40, 50), the degree of uptake would not lead to substantially higher net intramuscular levels compared with the control situation. For relative comparison, Bangsbo et al. (3) showed that an exercise-induced increase in venous plasma lactate from 1.5 to 7.5 mM increased resting intramuscular lactate levels from 1.9 to 3.5 mmol/kg wet muscle. Moreover, it is also worth considering differences between men and women. The women had lower postexercise muscle lactate levels in the Saline trial compared with the men (5.0 vs. 7.4 mmol/L i.c. water, P = 0.002). Conversely, the women exhibited greater between-trial differences in peak plasma lactate levels compared with the men (5.1 vs. 3.9 mmol/L). If assuming similar endogenous lactate production in both trials, the women accordingly had a greater plasma-to-muscle lactate gradient in the Lactate trial compared with the men. Consequently, the between-trial differences in intramuscular lactate levels were 23% for the women and 13% for the men. Thus, an estimated plasma-to-muscle gradient of 4.1 mmol/L for the women and 1.3 mmol/L for the men postexercise in the Lactate trial led to quite a small effect on intramuscular lactate levels. This indicates large plasma-to-muscle gradient required to obtain a significant elevation of intramuscular lactate levels under these conditions.

When evaluating blood and muscle lactate exchange, the alkalizing effect of blood by the sodium lactate infusion must also be considered. Miller et al. (35) concluded that the major contributor to the shift in pH with sodium lactate infusion is the increased level of blood sodium, which increases the strong ion difference and thereby lowers [H+]. Additionally, tissue removal and oxidation of the infused lactate from the blood also contribute to H+ removal from the blood due to lactate-H+ cotransport (26). Although there were large differences in blood pH between trials, there were no differences in postexercise muscle pH. It should be noted that our resting muscle pH values were higher than the normally observed value of 7.1. This could be attributed to methodological aspects such as freeze-drying, which is shown to increase pH (20). However, resting muscle pH levels above 7.2 have been reported in the literature (24, 45), and we found strong correlations between muscle pH and lactate levels. Nevertheless, in the Lactate trial, the muscle-to-blood H+ gradient was markedly increased, which should have stimulated an increased muscle H+ release and consequently lactate release (44). Thus, taken together, the small plasma-to-muscle lactate gradient and the increased muscle-to-blood H+ gradient likely contributed to the lack of a substantial elevation of intramuscular lactate levels in the Lactate trial.

It could be argued that the lack of influence by lactate on the assessed signaling events was due to an insufficient increase in intramuscular lactate levels. Considering available in vivo data, Kitaoka et al. (27) and Cerda-Kohler et al. (10) showed that a single intraperitoneal sodium lactate injection in mice at rest, resulting in peak blood lactate levels of almost 20 mM, stimulated skeletal muscle cell signaling events and mRNA expression. However, it is uncertain whether these observed effects were due to elevated muscle levels of lactate because that was not assessed in these studies. As noted above, an exercise-induced eightfold increase in blood lactate has been shown to result in an ∼80% increase in resting human muscle lactate levels, an effect that was mainly attributed to the exercise-induced increase in blood flow to the resting muscle (3). Thus, muscle lactate-dependent effects seem questionable because no marked lactate accumulation is likely to occur in uncontracted muscle with resting rates of blood flow. It could also be argued that lactate is mainly produced within a contracting muscle and would consequently exert its potential effects through an intracellular mechanism. However, lactate that is produced and released in a working muscle will both recirculate to the muscle (40, 50) and be present within the muscle’s microcirculation, thus leading to significant extracellular exposure for the working muscle. Finally, data from Ohno et al. (38) showed that lactate-induced ERK signaling in C2C12 cells was dependent on activation of the lactate-sensitive GPR81 located on the cell surface (30). Taken together, at present, the data do not support that a directly induced signaling response to lactate is dependent on intramuscular levels per se.

Because the sodium lactate infusion led to a substantial increase in blood pH, we must also acknowledge the potential impact of pH on muscle cell signaling responses. At present, there is very limited data concerning whether and how alterations in pH affect signaling events in skeletal muscle cells. A reduced pH has been shown to dampen Akt-signaling in L6 myocytes (15) and reduce exercise-induced mRNA expression in human skeletal muscle (13). In these studies, reduced cell media pH and blood pH were also shown to result in a reduced intracellular pH. Taken together, it is uncertain but not that likely that the increased blood pH, which did not affect muscle pH, may have affected the signaling events in the present study, thereby reducing or abolishing the anabolic effect of lactate.

The finding that increased systemic levels of lactate did not modulate the signaling response for any of the assessed targets could also have occurred because the potential effects were studied in contracted muscle. It is possible that the loaded muscle contractions induced a potent stimulatory effect that could not be further augmented by lactate. Indeed, all previous in vitro studies and most studies performed on rodents have been conducted on noncontracted muscle cells. Thus, it could be argued that the potential signaling effects of lactate in human skeletal muscle are small to modest and lose significance upon a potent loaded contractile stimulus. The rationale for performing this investigation on exercised and not resting muscle was to make it practically relevant because major systemic lactate accumulation does not occur in healthy humans without muscle contractions. Moreover, exercise also robustly increases blood flow to the contracting limb, which in turn increases lactate delivery to the studied muscle. Although there are no previous data on potential acute lactate signaling in contracted muscle cells, Oishi et al. (39) showed that oral sodium lactate administration to rats combined with exercise for four weeks resulted in higher muscle weights and protein content of myogenin and follistatin compared with exercised controls. However, it was not realistic for us to include additional resting trials for both sodium lactate and saline infusion, and therefore it remains unanswered whether muscle contractions override the potential signaling properties of lactate.

Separating women and men in the analysis with regard to the cell signaling events did not modulate any between-trial effects, indicating that under these conditions, lactate does not affect mTORC1 or ERK signaling, regardless of sex. Cerda-Kohler et al. (10) showed that lactate treatment stimulated S6K1 and p44 phosphorylation in mainly glycolytic but not in oxidative mouse muscle. In the present study, women had a significantly higher MHC I composition than men, which indicated that there could be differences in the response to lactate treatment between the sexes. However, the differences in MHC composition were small compared with the differences between the quadriceps and soleus of mice, and we also found no indications that subjects with very high or low MHC II% responded in a certain way to the lactate treatment.

We chose to assess the muscle protein FSR over 24 h using D2O, in part because we wanted to attain a nonlaboratory measure of exercise-induced protein synthesis in nonresting and feeding-induced states. Moreover, we recently showed that the variability in the FSR assessed with 13C6-phenylalanine increases with repeated infusions (22) and therefore is unsuitable when potential between-trial differences are expected to be small to modest. We also aimed to measure short-term FSR over 4 h of exercise and recovery because Wilkinson et al. (52) showed agreement between D2O and 13C6-Phe for determining amino acid-induced FSR over 3 h. D2O has also been utilized to measure feeding plus exercise-induced FSR over 4 h (16). However, when we measured the FSR over 4 h of exercise and recovery (pre- to 180 min postexercise), the variation was substantial, with values ranging from −0.075–0.390%/h and with only five values in the commonly reported range of 0.05–0.15%/h. The 2H-alanine was too low and was possibly affected by the exercise-induced glycogen to alanine production (49), thereby causing differences in the alanine precursor enrichments and affecting robust increases in protein enrichment over 3–4 h under fasted exercise conditions. Both plasma and intracellular precursor enrichment and analytic sensitivity were high, and the data obtained for the 24-h assessment were robust because the relatively short exercise-induced disturbances on the alanine precursor enrichment are small on the 24-h period. Thus, in our opinion, the D2O approach is solid for FSR assessment but not under very limited time periods such as 3–4 h, particularly under fasting exercise conditions. We argue the need for further validation of the use of D2O for measuring short-term FSR under similar conditions.

The model utilized in this study has limitations because modulating a single physiological variable in humans in vivo is complex. We therefore want to emphasize that this study should be seen as a first attempt to investigate the potential role of lactate in human tissue in vivo. The crossover design with 16 subjects, postexercise time course of biopsy sampling, matched exercise conditions, and marked between-trial differences in systemic lactate are the major strengths that support our findings. To further support our understanding of the potential role of lactate in anabolic signaling, a model where systemic lactate would be elevated well above 10 mM, without significantly altering other physiological variables, would be beneficial. Data about the arterial delivery of lactate to the studied muscle would also be of great value. The impact of fiber type and the impact of contracted versus noncontracted muscle are also vital aspects that require further study.

In conclusion, using a novel experimental design, we aimed to investigate the potential anabolic cell signaling properties of lactate in relation to resistance exercise in human skeletal muscle. Venous infusion of sodium lactate led to 130% higher systemic levels of lactate compared with the control trial during resistance exercise. There were, however, no differences between the Lactate and Saline trials with regard to exercise-induced mTORC1 or ERK signaling in any of the four postexercise biopsies sampled from the vastus lateralis of the male and female subjects. Our data do not conform to recent in vitro and rodent model data and suggest that lactate does not possess anabolic signaling properties in contracted human muscle. We propose that future investigations study the influence of the degree of lactatemia, intramuscular levels, fiber type, and contracted compared with rested muscle.


This project has been funded by grants to M. Moberg from the Swedish Research Council for Sport Science (nos. 2017-0038 and 2019-0061). M. Moberg is also funded through an Early Career Research Fellowship from the Swedish Research Council for Sport Science (no. D2017-0012). W. Apró was funded through an Early Career Research Fellowship from the Swedish Research Council for Sport Science (no. D2019-0050).


No conflicts of interest, financial or otherwise, are declared by the authors.


G.v.H., H.H., and M.M. conceived and designed research; R.L., W.A., B.E., and M.M. performed experiments; R.L., S.D., G.v.H., and M.M. analyzed data; W.A., G.v.H., and M.M. interpreted results of experiments; M.M. prepared figures; M.M. drafted manuscript; R.L., W.A., B.E., G.v.H., H.H., and M.M. edited and revised manuscript; R.L., W.A., S.D., B.E., G.v.H., H.H., and M.M. approved final version of manuscript.


We acknowledge APL Sweden for technical assistance in producing sodium lactate suitable for infusion.


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