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Objective It is well known that a bout of resistance exercise stimulates mechanistic target of rapamycin complex 1 (mTORC1) signaling and the rate of protein synthesis in skeletal muscle, which after repeated stimulus ultimately leads to muscle hypertrophy. However, the precise molecular events that leads to the activation of mTORC1 and protein synthesis following resistance exercise remains to be elucidated. A number of previous studies have shown that resistance exercise protocols that cause a significant degree of metabolic stress, such as blood flow restriction or low-load repetitions to failure, activate mTORC1 and protein synthesis, as well as induce muscle growth, to a similar extent as conventional high-load muscle contractions. It is suggested that the accumulated metabolites are responsible for the anabolic response in those intense and stressful exercise protocols, either as direct signaling molecules or indirectly e.g. by enhancing fiber activation. Here, one metabolite is of particular interest, namely lactate. Interestingly, it has been shown that incubation of C2C12 myotubes with lactate increases mTORC1 signaling and reduces myostatin expression. Moreover, in vitro lactate incubation has been shown to induce the expression of peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α), suggestively through increased reactive oxygen species production. The latter is also of interest since intense high volume resistance exercise can activate AMP-activated protein kinase (AMPK) and induce PGC-1α expression. Accordingly the purpose of the present study is to investigate the acute molecular response in human skeletal muscle to resistance exercise performed with our without a venous infusion of sodium lactate. The objective was to create a situation where muscle contractions were performed with low or high levels of lactate and where other factors such as load, volume, time under tension, hormonal levels and etc. would not differ between interventions. The primary outcomes of the study is analysis of intracellular signaling, rate of muscle protein synthesis (FSR), mRNA expression as well as blood and muscle levels of lactate and pH. Methods Four female and four male, young and healthy, subjects who performed resistance exercise of the lower body on a regular basis participated in the study. Following pre-testing subjects performed two familiarization sessions and two experimental trials, with each session separated by seven to ten days. The experimental trials consisted of unilateral knee-extension resistance exercise performed under venous infusion of sodium lactate or saline (placebo), in a randomized counterbalanced fashion, where subjects were blinded to the treatment. On the days before the trials subjects consumed an oral dose of deuterium oxide to enable measurement of muscle protein synthesis rates during recovery. On the day of the trials subjects reported to the laboratory at 0700 hours in the fasted state, had their blood status cleared and donated a first muscle biopsy from the vastus lateralis. There after an infusion of sodium lactate or saline was initiated at rest, and following 20 min of infusion subjects performed a bout of unilateral knee extension exercise. Immediately after exercise completion the infusion was terminated and a second muscle biopsy was taken. This was followed by a three hour recovery period where additional biopsies were taken at 90 and 180 min post exercise. Blood samples were drawn repeatedly in 10-30 min intervals throughout the trial. After the three hours of recovery subjects ingested a standardized meal, left the laboratory to be free-living and then return to the lab in the overnight fasted state the next morning for a 24 h muscle biopsy which concluded the trial.Whole blood levels of lactate, glucose, sodium, potassium as well as base excess and pH were analyzed in each sample immediately after collection. Muscle levels of lactate were analyzed on lyophilized and dissected muscle samples. Immunoblotting was used to analyze mTORC1-, AMPK- and MAPK signaling. Analysis of 2H-alanine using mass spectrometry enabled calculation of muscle protein FSR during 3h and 24h post exercise. Muscle pH and mRNA expression remains to be determined. Results Load, number of repetitions and time under tension during resistance exercise did not differ between trials. No subject was able to identify in which trial the received the sodium lactate infusion. In the placebo trial blood levels of lactate increased during exercise to 3.00 ± 0.28 mmol/l and remained higher than at baseline up until 45 min post exercise (P