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Gi-coupled protein receptor 81 (GPR81) was first identified in adipocytes as a receptor for l-lactate, which upon binding inhibits cyclicAMP (cAMP)-protein kinase (PKA)-cAMP-response element binding (CREB) signaling. Moreover, incubation of myotubes with lactate augments expression of GPR81 and genes and proteins involved in lactate- and energy metabolism. However, characterization of GPR81 expression and investigation of related signaling in human skeletal muscle under conditions of elevated circulating lactate levels are lacking. Muscle biopsies were obtained from healthy men and women at rest, after leg extension exercise, with or without venous infusion of sodium lactate, and 90 and 180 min after exercise (8 men and 8 women). Analyses included protein and mRNA levels of GPR81, as well as GPR81-dependent signaling molecules. GPR81 expression was 2.5-fold higher in type II glycolytic compared with type I oxidative muscle fibers, and the expression was inversely related to the percentage of type I muscle fibers. Muscle from women expressed about 25% more GPR81 protein than from men. Global PKA activity increased by 5%–8% after exercise, with no differences between trials. CREBS133 phosphorylation was reduced by 30% after exercise and remained repressed during the entire trials, with no influence of the lactate infusion. The mRNA expression of vascular endothelial growth factor (VEGF) and peroxisome-proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) were increased by 2.5–6-fold during recovery, and that of lactate dehydrogenase reduced by 15% with no differences between trials for any gene at any time point. The high expression of GPR81-protein in type II fibers suggests that lactate functions as an autocrine signaling molecule in muscle; however, lactate does not appear to regulate CREB signaling during exercise.

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.

Background: The amount of muscle mass or muscle volume (MV) varies between individuals and is important for health, wellbeing, and performance. Imaging is a useful tool to monitor MV, magnetic resonance imaging (MRI) is considered gold standard. MRI are not always easily accessible, and the measurements are expensive, therefore ultrasonography (US) has become a more accessible method for estimating MV. Methods: A systematic literature review was conducted in the electronic databases PubMed, CINHAL and Web of Science with the purpose of collecting the current published equations to estimate MV with US and answering the following question: How well does US derived equations based on muscle thickness (MT) predict MV based on MRI? Results: The literature search resulted in 363 citations. Twelve articles met the eligibility criteria and were included. Ten articles scored eight out of eleven on the QUADAS score and two scored nine out of eleven. 36 different prediction equations were identified. Correlations were good, r values ranged between 0.53-0.961 and the standard error of estimates (SEE) ranged between 6-25.6%. Eight studies did further analysis with a Bland-Altman plot and found no systematic errors. The overall strength and quality of the evidence was rated as “low quality” as defined by the GRADE system. Conclusions: We conclude that the validity of US derived equations based on MT is specific to the populations from where it is developed. The agreement with MV based on MRI is moderate with SEE ranging between 6-12% in healthy populations. Suggestions for future research are to investigate if testing positions or increasing the number of measuring points could improve the validity for prediction equations.

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