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Hoffman JR et al. Efficacy of phosphatidic acid ingestion on lean body mass, muscle thickness and strength gains in resistance-trained men. J Int Soc Sports Nutr. 2012 Oct 5;9(1):47. doi: 10.1186/1550-2783-9-47. ABSTRACT: Background: Phosphatidic acid (PA) has been reported to activate the mammalian target of rapamycin (mTOR) signaling pathway and is thought to enhance the anabolic effects of resistance training. The purpose of this pilot study was to examine if oral phosphatidic acid administration can enhance strength, muscle thickness and lean tissue accruement during an 8-week resistance training program. Methods: Sixteen resistance-trained men were randomly assigned to a group that either consumed 750 mg of PA (n = 7, 23.1 ± 4.4 y; 176.7 ± 6.7 cm; 86.5 ± 21.2 kg) or a placebo (PL, n = 9, 22.5 ± 2.0 y; 179.8 ± 5.4 cm; 89.4 ± 13.6 kg) group. During each testing session subjects were assessed for strength (one repetition maximum [1-RM] bench press and squat) and body composition. Muscle thickness and pennation angle were also measured in the vastus lateralis of the subject’s dominant leg. Results: Subjects ingesting PA demonstrated a 12.7% increase in squat strength and a 2.6% increase in LBM, while subjects consuming PL showed a 9.3% improvement in squat strength and a 0.1% change in LBM. Although parametric analysis was unable to demonstrate significant differences, magnitude based inferences indicated that the Δ change in 1-RM squat showed a likely benefit from PA on increasing lower body strength and a very likely benefit for increasing lean body mass (LBM). Conclusions: Results of this study suggest that a combination of a daily 750 mg PA ingestion, combined with a 4-day per week resistance training program for 8-weeks appears to have a likely benefit on strength improvement, and a very likely benefit on lean tissue accruement in young, resistance trained individuals.
Joy JM et al. Phosphatidic acid enhances mTOR signaling and resistance exercise induced hypertrophy. Nutr Metab (Lond). 2014 Jun 16;11:29. doi: 10.1186/1743-7075-11-29. ABSTRACT: Introduction: The lipid messenger phosphatidic acid (PA) plays a critical role in the stimulation of mTOR signaling. However, the mechanism by which PA stimulates mTOR is currently unknown. Therefore, the purpose of this study was to compare the effects of various PA precursors and phospholipids on their ability to stimulate mTOR signaling and its ability to augment resistance training-induced changes in body composition and performance. Methods: In phase one, C2C12 myoblasts cells were stimulated with different phospholipids and phospholipid precursors derived from soy and egg sources. The ratio of phosphorylated p70 (P-p70-389) to total p70 was then used as readout for mTOR signaling. In phase two, resistance trained subjects (n = 28, 21 ± 3 years, 77 ± 4 kg, 176 ± 9 cm) consumed either 750 mg PA daily or placebo and each took part in an 8 week periodized resistance training program. Results: In phase one, soy-phosphatidylserine, soy-Lyso-PA, egg-PA, and soy-PA stimulated mTOR signaling, and the effects of soy-PA (+636%) were significantly greater than egg-PA (+221%). In phase two, PA significantly increased lean body mass (+2.4 kg), cross sectional area (+1.0 cm), and leg press strength (+51.9 kg) over placebo. Conclusions: PA significantly activates mTOR and significantly improved responses in skeletal muscle hypertrophy, lean body mass, and maximal strength to resistance exercise.
Joy JM et al. Phosphatidic acid supplementation increases skeletal muscle hypertrophy and strength. J Int Soc Sports Nutr. 2013; 10(Suppl 1): P13. doi: 10.1186/1550-2783-10-S1-P13. ABSTRACT: Introduction: The accretion of skeletal muscle tissue can be critical for a varied population including athletes and elderly. Skeletal muscle hypertrophy is largely mediated through increased muscle protein synthesis. The mammalian target of rapamycin (mTOR) has been shown to regulate rates of muscle protein synthesis and a mechanical stimulus (resistance exercise) has been shown to activate mTOR with the phospholipid Phosphatidic Acid (PA) playing a key role. A first pilot study found that oral supplementation with soy-derived PA in athletes undergoing progressive resistance training very likely resulted in greater increases in squat strength and lean mass over the placebo. However, this pilot study was likely underpowered, the workout was not supervised and no direct measures of skeletal muscle hypertrophy were taken. Therefore, the purpose of this study was to investigate the effects of PA on body composition, strength, power and muscular hypertrophy. Methods: Twenty-eight resistance trained, male subjects (21 ± 3 years of age, bodyweight of 76 ± 9 kg, and height of 176 cm ± 9 cm) participated in this study. Subjects were equally divided into experimental and control conditions, and each subject took part in an 8 week periodized resistance training program. The resistance training program consisted of two hypertrophy oriented workouts per week and one strength oriented workout per week. The experimental condition (EXP) received 750 mg of soy-derived PA (Mediator™, Chemi Nutra, White Bear Lake, MN), while the control condition (CON) received a visually identical placebo (rice flour). Measurements of DEXA-determined body composition, rectus femoris CSA, 1RM strength, and anaerobic power were taken prior to and following the 8 week training intervention. A 2x2 repeated measures ANOVA was used to determine group, time, and group x time interactions. A Tukey post-hoc was used to locate differences. Results: There was a significant group x time effect (p=0.02) for CSA, in which the EXP group increased (+1.01 cm2, ES = 0.92) to a greater extent than the CON group (+0.61 cm2, ES = 0.52). There was a significant group x time effect (p=0.01) for LBM, in which the EXP group (+2.4 kg, ES = 0.42) doubled the effects of resistance training alone (CON +1.2 kg, ES = 0.26). There was a significant group x time effect (p=0.04) for leg press 1RM, in which the EXP group increased to a greater extent (+52.0 kg, ES = 1.2) than the CON group (+32.5 kg, ES = 0.78). There was a trend group x time effect (p=0.06) for fat loss, in which the EXP group decreased body fat to a greater extent than the CON group (-1.3kg vs. -0.5kg). Conclusions: Supplementation with soy-derived PA can improve responses in skeletal muscle hypertrophy, lean body mass, and maximal strength.
Joy JM et al. The effects of 8 weeks of phosphatidic acid supplementation on cardiovascular, kidney, and liver safety in health young males. Poster presented at the 2013 annual ISSN conference. ABSTRACT: Background: The mammalian target of rapamycin (mTOR) has been shown to regulate rates of muscle protein synthesis, and one novel nutritional activator of mTOR is the phospholipid Phosphatidic Acid (PA). We have recently found that PA supplementation over 8 weeks of resistance training augmented responses in skeletal muscle hypertrophy and strength. However, we are unaware of research investigating the safety of PA in human subjects. Therefore the purpose of this study was to investigate the effects of 8 weeks of 750 mg per day of PA supplementation on safety parameters in healthy college aged males. Methods: Twenty-eight healthy, college aged male subjects (21 ± 3 years of age, bodyweight of 76 ± 9 kg, and height of 176 cm ± 9 cm) participated in this study. Subjects were equally divided into experimental and control conditions. The experimental condition (EXP) received 750 mg of soy-derived PA (Mediator™, Chemi Nutra, White Bear Lake, MN), while the control condition (CON) received a visually identical placebo (rice flour). Measures of cardiovascular, kidney, and liver function were analyzed with a full CMP and CBC prior to and 8 weeks following supplementation. This analysis included: total, high density, and low density lipoproteins, blood glucose, blood urea nitrogen, creatinine, eGFR, Na, K, Cl, CO2, Ca, protein, albumin, globulin, albumin:globulin ratio, total bilirubin, alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase. In addition a sample of urine was submitted for analysis of urine specific gravity and pH. A 2x2 repeated measures ANOVA was used to determine group, time, and group x time interactions. A Tukey post-hoc was used to locate differences. Results: There were no differences at baseline in blood chemistry and hematology between the CON and EXP supplemented groups. Additionally no differences were observed in urinalysis values between the groups. Moreover no group, or group X time effects were found following 8 weeks of supplementation. Conclusions: Soy-derived PA is a safe nutritional supplement for healthy college aged subjects if taken up to a dosage of 750 mg over an eight week period.
Fang Y et al. Phosphatidic Acid-Mediated Mitogenic Activation of mTOR Signaling. Science 30 Nov 2001: Vol. 294, Issue 5548, pp. 1942-1945. doi: 10.1126/science.1066015. ABSTRACT: The mammalian target of rapamycin (mTOR) governs cell growth and proliferation by mediating the mitogen- and nutrient-dependent signal transduction that regulates messenger RNA translation. We identified phosphatidic acid (PA) as a critical component of mTOR signaling. In our study, mitogenic stimulation of mammalian cells led to a phospholipase D–dependent accumulation of cellular PA, which was required for activation of mTOR downstream effectors. PA directly interacted with the domain in mTOR that is targeted by rapamycin, and this interaction was positively correlated with mTOR's ability to activate downstream effectors. The involvement of PA in mTOR signaling reveals an important function of this lipid in signal transduction and protein synthesis, as well as a direct link between mTOR and mitogens. Furthermore, these studies suggest a potential mechanism for the in vivo actions of the immunosuppressant rapamycin.
Gundermann D et al. Soy-derived Phosphatidic Acid, Lysophosphatidic acid and Phosphatidylserine are sufficient to induce an increase in mTOR signaling J Int Soc Sports Nutr. 2013; 10(Suppl 1): P7. doi: 10.1186/1550-2783-10-S1-P7. ABSTRACT: Background: A protein kinase called the mechanistic target of rapamycin (mTOR) is a well-known regulator of cellular growth. In fact, several studies have indicated that the kinase activity of mTOR is required for mechanically-induced increases in skeletal muscle protein synthesis and hypertrophy. Previous studies have also determined that the lipid messenger phosphatidic acid (PA) plays a critical role in the stimulation of mTOR signaling and, an increase in PA concentration is sufficient for the activation of mTOR signaling. However, the mechanism by which PA stimulates mTOR is currently unknown. A primary target of mTOR includes the phosphorylation of p70 on the threonine 389 residue (P-p70-389), and thus, is a commonly accepted readout for the activation of mTOR. PA can be synthesized from a variety of reactions via multiple reactants. Therefore, the purpose of this study was to compare the effects of various PA precursors on their ability to stimulate mTOR signaling and determine if any other phospholipid species are also capable of stimulating mTOR signaling. Methods: C2C12 myoblasts were plated at approximately 30% confluence and grown for 24 hours in 10% FBS High Glucose DMEM. Cells were switched to 2mL/well serum free high glucose DMEM (no antibiotics) for 16 hours prior to the experiment. Cells were approximately 70% confluent at the time of the experiment. Cells were then stimulated for 20 minutes with vehicle (Control) or 10, 30 or 100µM of soy-derived phosphatidylserine (S-PS, SerinAid, Chemi Nutra, White Bear Lake, MN), phosphatidylinositol (S-PI), phosphatidylethanolamine (S-PE), phosphatidylcholine (S-PC), PA (S-PA, Mediator, Chemi Nutra, White Bear Lake, MN), lysophosphatidic acid (S-LPA), diacylglycerol (DAG), glycerol-3-phosphate (G3P), and egg-derived PA (E-PA). Cells were harvested in lysis buffer and subjected to immunoblotting. The ratio of P-p70-389 to total p70 was used as readout for mTOR signaling. Results: S-PI, S-PE, S-PC, DAG, and G3P elicited no increase in the ratio of P-p70-389 to total p70 compared to vehicle stimulated cells. In contrast, elevated mTOR signaling was observed at all tested concentrations of S-PS (529, 588, and 457%), S-LPA (649, 866, and 1,132%), and S-PA (679, 746, and 957%; P > 0.05). Egg-PA induced an 873% increase in mTOR signaling with the 100µM dose (P > 0.05), whereas no significant increase was observed with the 10 or 30µM doses. Conclusions: S-PA, S-LPA and S-PS are each sufficient to induce an increase in mTOR signaling. Therefore, they may be capable of enhancing the anabolic effects of resistance training and contributing to muscle accretion over time. Furthermore, S-PA is a more potent stimulator of mTOR signaling than PA derived from egg.
Purpura M et al. Effect of oral administration of soy-derived phosphatidic acid on concentrations of phosphatidic acid and lyso-phosphatidic acid molecular species in human plasma. J Int Soc Sports Nutr. 2013; 10(Suppl 1): P22. doi: 10.1186/1550-2783-10-S1-P22. ABSTRACT: Background: The glycerophospholipid Phosphatidic acid (PA) has been identified as a potential nutritional treatment for gastrointestinal disorders. Dietary food sources rich in PA include cabbage and radish leaves as well as Mallotus japonicas, a Japanese edible herb historically used for the treatment of stomach ulcers. The mammalian target of rapamycin (mTOR) has been shown to regulate rates of muscle protein synthesis and a mechanical stimulus (resistance exercise) has been shown to activate mTOR with PA playing a key role. Supplementation with soy-derived PA significantly increases responses in skeletal muscle hypertrophy, lean body mass, and maximal strength to resistance exercise. PA accounts for less than 0.1% of the total glycerophospholipid concentration of 201 mg/dl in the human plasma. 15 of the more than 600 distinct molecular lipid species quantified in human plasma are PA, 6 are lysophosphatidic acid (LPA). Orally administered PA can be metabolized to LPA and glycerophosphate by pancreatic phospholipases A1 and A2, which hydrolyze the fatty acid at the sn-1 position and the sn-2 position, respectively. Lysophospholipids are absorbed by the mucosal cells of the gastrointestinal tract and are rapidly re-acylated with fatty acids of the body pool resulting in a newly-formed phospholipid-molecule whose fatty acid composition is determined by the physiological and nutritional status and not by its source. This study sought to assess the effect of soy-derived PA supplementation on concentrations LPA and PA molecular species in human plasma. Methods: After a 12 hour overnight fast one subject (20 years of age, bodyweight of 82 kg, and height of 178 cm) was assigned to receive 1.5 grams of soy-derived PA (Mediator, Chemi Nutra, White Bear Lake, MN). Blood draws were taken immediately prior to, and at 30 min, 1, 2, 3, and 7 hours following supplementation. The samples were analyzed by an ultra-performance liquid chromatograph with triple quadrupole mass spectrometry (LC/MS/MS) using 17:1-LPA and 37:4-PA as internal standards to determine the concentration of LPA and PA molecular species in human plasma. Results: At baseline, 19 PA (highest concentrations: C34:2 (15%), C40:4 (11%), and C36:4 (10%)) and 5 LPA (16:0 (45%), 18:2 (19%), 20:4 (17%), 14:0 (11%) and 18:1 (8%)) molecular species could be quantified with total concentrations of PA of 2.66 nmol/ml, and LPA of 0.11 nmol/ml. Plasma concentrations of PA peaked at 3 hours (+32%) after ingestion and stayed elevated even after 7 hours (+18%). LPA showed a bimodal absorption kinetic with peaks after 1 hour (+500%) and 3 hours (+264%), after almost dropping back to baseline levels after 2 hours. On an individual fatty acid level, most prominent was a 23-fold increase in 20:4-LPA after 1 hour compared to baseline. The increase in 20:4-LPA does not result from the administration of PA, since soy-derived PA does not contain any arachidonic acid (fatty acids distribution of soy-PA: 18:2 (66.1%), 18:1 (12.6%), 16:0 (11.7%), 18:3 (6.1%) and 18:0 (3.4%)). Absorption of soy-derived PA must yield glycerophosphate which is re-acylated with arachidonic acid. Conclusion: LPA and PA can be molecularly identified and measured. LPA, PA and LPA+PA plasma levels increase 30 min after ingestions, plateau at 1-3 hours and remain above baseline levels after 7 hours. This is the first case study showing that orally administered PA is bioavailable. Future research should repeat this case study with a larger n-size and include the analysis of omega 3 fatty acid-LPA molecular species.
Hornberger TA et al. The role of phospholipase D and phosphatidic acid in the mechanical activation of mTOR signaling in skeletal muscle. Proc Natl Acad Sci U S A. 2006 Mar 21; 103(12): 4741–4746. doi: 10.1073/pnas.0600678103. ABSTRACT: Signaling by the mammalian target of rapamycin (mTOR) has been reported to be necessary for mechanical load-induced growth of skeletal muscle. The mechanisms involved in the mechanical activation of mTOR signaling are not known, but several studies indicate that a unique [phosphotidylinositol-3-kinase (PI3K)- and nutrient-independent] mechanism is involved. In this study, we have demonstrated that a regulatory pathway for mTOR signaling that involves phospholipase D (PLD) and the lipid second messenger phosphatidic acid (PA) plays a critical role in the mechanical activation of mTOR signaling. First, an elevation in PA concentration was sufficient for the activation of mTOR signaling. Second, the isozymes of PLD (PLD1 and PLD2) are localized to the z-band in skeletal muscle (a critical site of mechanical force transmission). Third, mechanical stimulation of skeletal muscle with intermittent passive stretch ex vivo induced PLD activation, PA accumulation, and mTOR signaling. Finally, pharmacological inhibition of PLD blocked the mechanically induced increase in PA and the activation of mTOR signaling. Combined, these results indicate that mechanical stimuli activate mTOR signaling through a PLD-dependent increase in PA. Furthermore, we showed that mTOR signaling was partially resistant to rapamycin in muscles subjected to mechanical stimulation. Because rapamycin and PA compete for binding to the FRB domain on mTOR, these results suggest that mechanical stimuli activate mTOR signaling through an enhanced binding of PA to the FRB domain on mTOR.
O'Neil TK et al. The role of phosphoinositide 3-kinase and phosphatidic acid in the regulation of mammalian target of rapamycin following eccentric contractions. J Physiol 581.14: 3691-3701, 2009. doi: 10.1113/jphysiol.2009.173609. ABSTRACT: Resistance exercise induces a hypertrophic response in skeletal muscle and recent studies have begun to shed light on the molecular mechanisms involved in this process. For example, several studies indicate that signalling by the mammalian target of rapamycin (mTOR) is necessary for a hypertrophic response. Furthermore, resistance exercise has been proposed to activate mTOR signalling through an upstream pathway involving the phosphoinositide 3-kinase (PI3K) and protein kinase B (PKB); however, this hypothesis has not been thoroughly tested. To test this hypothesis, we first evaluated the temporal pattern of signalling through PI3K-PKB and mTOR following a bout of resistance exercise with eccentric contractions (EC). Our results indicated that the activation of signalling through PI3K-PKB is a transient event (> 15 min), while the activation of mTOR is sustained for a long duration (> 12 h). Furthermore, inhibition of PI3K-PKB activity did not prevent the activation of mTOR signalling by ECs, indicating that PI3K-PKB is not part of the upstream regulatory pathway. These observations led us to investigate an alternative pathway for the activation of mTOR signalling involving the synthesis of phosphatidic acid (PA) by phospholipase D (PLD). Our results demonstrate that ECs induce a sustained elevation in [PA] and inhibiting the synthesis of PA by PLD prevented the activation of mTOR. Furthermore, we determined that similar to ECs, PA activates mTOR signalling through a PI3K-PKB-independent mechanism. Combined, the results of this study indicate that the activation of mTOR following eccentric contractions occurs through a PI3K-PKB-independent mechanism that requires PLD and PA.
Winter JN et al. Phosphatidic acid mediates activation of mTORC1 through the ERK signaling pathway. Am J Physiol Cell Physiol 299: C335-C344, 2010. doi: 10.1152/ajpcell.00039.2010. ABSTRACT: The mammalian target of rapamycin (mTOR) assembles into two distinct multiprotein complexes known as mTORC1 and mTORC2. Of the two complexes, mTORC1 acts to integrate a variety of positive and negative signals to downstream targets that regulate cell growth. The lipid second messenger, phosphatidic acid (PA), represents one positive input to mTORC1, and it is thought to act by binding directly to mTOR, thereby enhancing the protein kinase activity of mTORC1. Support for this model includes findings that PA binds directly to mTOR and addition of PA to the medium of cells in culture results in activation of mTORC1. In contrast, the results of the present study do not support a model in which PA activates mTORC1 through direct interaction with the protein kinase but, instead, show that the lipid promotes mTORC1 signaling through activation of the ERK pathway. Moreover, rather than acting directly on mTORC1, the results suggest that exogenous PA must be metabolized to lysophosphatidic acid (LPA), which subsequently activates the LPA receptor endothelial differentiation gene (EDG-2). Finally, in contrast to previous studies, the results of the present study demonstrate that leucine does not act through phospholipase D and PA to activate mTORC1 and, instead, show that the two mediators act through parallel upstream signaling pathways to activate mTORC1. Overall, the results demonstrate that leucine and PA signal through parallel pathways to activate mTORC1 and that PA mediates its effect through the ERK pathway, rather than through direct binding to mTOR.