1. Citrulline Malate H2NH2N NH OO NH 2 OH L-citrulline O HO O OH Malate (Malic acid)

2. Introduction L-citrulline is a non essential amino acid Malate is an intermediate of the tricarboxylic acid cycle (TCA) Originally developed: 1. Improve muscle performance for asthenia sufferers 2. Improve recovery time from physical activity for individuals with acute diseases Recent research for athletic population: 1. Enhances aerobic energy production 2. Augment muscle force output 3. Mitigate muscle fatigue (Wax et al., 2015)

3. How it works 3 proposed mechanisms of action: 1. Excess availability of citrulline allows the acceleration of the urea cycle therefore facilitating the clearance of ammonium. 2. Malate acts as an metabolic shuttle between cytoplasm and mitochondria. 3. Nitric Oxide (NO) regulates glucose uptake and oxidation, mitochondriogenesis, contractile functions, blood flow, fatty acid oxidation and muscle repair in skeletal muscle. (Pérez-Guisado and Jakeman, 2010)

4. Citrulline Malate on Aerobic Energy Production (Bendahan et al., 2002)

5. Citrulline Malate on Aerobic Energy Production BeforeDuringAfter Rate of oxidative ATP production (%EC) 54 (12)74 (4)45 (6) BeforeDuringAfter Vi rec 16.9 (2.9) 24.2 (3.2) 16.4 (1.9) (Bendahan et al., 2002)

6. Bendahan et al. (2002) Conclusions Rate of muscle oxidative ATP production during exercise increase with CM supplementation Rate of PCr recovery after exercise increased with CM supplementation (Bendahan et al., 2002)

7. (Nissim et al., 2003) How it works

8. Citrulline Malate on Recovery & Fatigue (López-Cabral et al., 2012)

9. Citrulline Malate on Recovery (López-Cabral et al., 2012)

10. Citrulline Malate on Fatigue (López-Cabral et al., 2012)

11. López-Cabral et al. (2012) Conclusions Expected results in recovery and fatigue are achieved quicker with 6g/day vs 3g/day dose although both have similar efficacy after 2weeks CM enhances lactate clearance and fatigue recovery of high performance athletes. (López-Cabral et al., 2012)

12. Citrulline Malate on Recovery (Sureda et al., 2010)

13. Citrulline Malate on Recovery CM raises plasma L-arginine concentration CM augments nitrite, creatine, ornithine and urea and hormones (GH) CM augments nitrogen availability allowing increases in protein synthesis and protein content in muscle during exercise (Sureda et al., 2010)

14. Sureda et al. (2010) Conclusions CM reduced and delayed the onset of the immunosuppressive mechanisms associated with intense exercise CM improves the recovery process from intense training therefore avoiding symptoms associated with overtraining. (Sureda et al., 2010)

15. Citrulline Malate on Performance & Muscle Soreness (Pérez-Guisado and Jakeman, 2010)

16. Citrulline Malate on Performance Reps (PL)Reps (CM)%IncreaseResponders Set 112.27 ± 0.4512.39 ± 0.490.978 (19.51%) Set 46.00 ± 1.617.05 ± 1.7317.5025 (60.97%) Set 19.24 ± 2.0810.32 ± 1.7511.6931 (75.60%) Set 43.59 ± 1.405.49 ± 1.5352.9241 (100%) (Pérez-Guisado and Jakeman, 2010)

17. Citrulline Malate on Muscle Soreness Muscle SorenessPLCM%Decrement 24hr post workout3.12 ± 0.601.88 ± 0.6439.74 48hr post workout3.90 ± 0.702.27 ± 0.6741.79 Muscle SorenessRespondersNon-respondersWorse 24hr post workout40 (97.56%)1 (2.44%)0 (0) 48hr post workout37 (90.24%)4 (9.76%)0 (0) (Pérez-Guisado and Jakeman, 2010)

18. Pérez-Guisado and Jakeman (2010) Conclusions CM reduces fatigue by increasing rate of oxidative ATP production during exercise and the rate of PCr recovery after exercise Single dose of CM 1hr prior to exercise is an effective ergogenic aid CM increases athletic performance in high intensity anaerobic exercise with short rest periods CM attenuates post exercise muscle soreness (Pérez-Guisado and Jakeman, 2010)

19. Citrulline Malate on Fatigue (Wax et al., 2015)

20. Citrulline Malate on Fatigue (Wax et al., 2015)

21. Citrulline Malate on Fatigue (Wax et al., 2015)

22. Wax et al. (2015) Conclusions CM improved fatigue thus allowing an increase in work capacity of 19% CM improved overall performance by 9% No influence on blood lactate from either CM or PL However 3 minute recovery between all sets and exercises could have allowed metabolic recovery whilst mitigating acidosis, lactate and ammonium accumulation in the working muscle (Wax et al., 2015)

23. Safety (López-Cabral et al., 2012; Pérez-Guisado and Jakeman, 2010; Sureda et al., 2010)

24. Dosage & Timing 8g 1hr prior (Wax et al., 2015; Pérez-Guisado and Jakeman, 2010)

25. Availability (AllMax Nutrition Citrulline Malate 2:1 at Bodybuilding.com, 2015; LiveLong Nutrition Citrulline Malate at Bodybuilding.com, 2015; Myprotein, 2015; PrimaForce Citrulline Malate at Bodybuilding.com, 2015)

26. Cost BrandCostNo Servings Serving Size Cost per Serving Prima Force £16.861002g17p Allmax Nutrition £12.82402g32p LiveLong Nutrition £16.21333g49p MyProtein£12.992502g5p (AllMax Nutrition Citrulline Malate 2:1 at Bodybuilding.com, 2015; LiveLong Nutrition Citrulline Malate at Bodybuilding.com, 2015; Myprotein, 2015; PrimaForce Citrulline Malate at Bodybuilding.com, 2015)

27. WADA & Informed Sport (Informed-sport.com, 2015; World Anti-Doping Agency, 2014)

28. WADA & Informed Sport (AllMax Nutrition Citrulline Malate 2:1 at Bodybuilding.com, 2015; Informed-sport.com, 2015; LiveLong Nutrition Citrulline Malate at Bodybuilding.com, 2015; Myprotein, 2015; PrimaForce Citrulline Malate at Bodybuilding.com, 2015; World Anti-Doping Agency, 2014)

29. Conclusions CM increases athletic performance in high intensity anaerobic exercise with short rest periods CM attenuates post exercise muscle soreness CM enhances lactate clearance and fatigue recovery of high performance athletes therefore avoiding symptoms associated with overtraining. Rate of muscle oxidative ATP production during exercise increase with CM supplementation Rate of PCr recovery after exercise increased with CM supplementation (Wax et al., 2015; López-Cabral et al., 2012; Pérez-Guisado and Jakeman, 2010; Sureda et al., 2010; Nissim et al., 2003; Bendahan et al., 2002)

30. Type of Athlete that would benefit Athletes looking to relieve post exercise muscle soreness Intensive training or preparation engaging anaerobic metabolism resulting in increased lactate, ammonia and acidosis High intensity anaerobic exercise with short rest periods such as; 1. Strength training 2. Sprint sessions (Wax et al., 2015; López-Cabral et al., 2012; Pérez-Guisado and Jakeman, 2010; Sureda et al., 2010; Nissim et al., 2003; Bendahan et al., 2002)

31. References AllMax Nutrition Citrulline Malate 2:1 at Bodybuilding.com, (2015). AllMax Nutrition Citrulline Malate 2:1 at Bodybuilding.com. [online] Bodybuilding.com. Available at: http://uk.bodybuilding.com/store/allmax- nutrition/citrulline-malate-2-1.html?&_requestid=159765 [Accessed 25 Apr. 2015]. Bendahan, D., Mattei, J., Confort-Gouny, S., Le Guern, M. and Cozzone, P. (2002). Citrulline/malate promotes aerobic energy production in human exercising muscle. British Journal of Sports Medicine, 36(4), pp.282-289. Informed-sport.com, (2015). Home | Informed-Sport. [online] Available at: http://informed-sport.com [Accessed 25 Apr. 2015]. LiveLong Nutrition Citrulline Malate at Bodybuilding.com, (2015). LiveLong Nutrition Citrulline Malate at Bodybuilding.com. [online] Bodybuilding.com. Available at: http://uk.bodybuilding.com/store/live/citrulline- malate.html?&_requestid=160020 [Accessed 25 Apr. 2015]. López-Cabral, J., Rivera-Cisneros, A., Rodríguez-Camacho, H., Sánchez-González, J., Serna-Sánchez, I. and Trejo-Trejo, M. (2012). Modification of fatigue indicators using citrulline malate for high performance endurance athletes. Rev Latinoamer Patol Clin, 59(4), pp.194-201. Myprotein, (2015). Citrulline Malate. [online] Available at: http://www.myprotein.com/sports- nutrition/citrulline-malate/10529326.html?autocomplete=productsuggestion [Accessed 25 Apr. 2015].

32. References Nissim, I., Horyn, O., Luhovyy, B., Lazarow, A., Daikhin, Y., Nissim, I. and Yudkoff, M. (2003). Role of the glutamate dehydrogenase reaction in furnishing aspartate nitrogen for urea synthesis: studies in perfused rat liver with 15N. Biochem. J., 376(1), p.179. Pérez-Guisado, J. and Jakeman, P. (2010). Citrulline Malate Enhances Athletic Anaerobic Performance and Relieves Muscle Soreness. Journal of Strength and Conditioning Research, 24(5), pp.1215-1222. PrimaForce Citrulline Malate at Bodybuilding.com, (2015). PrimaForce Citrulline Malate at Bodybuilding.com. [online] Bodybuilding.com. Available at: http://uk.bodybuilding.com/store/prima/citrullinemalate.html?&_requestid=159677 [Accessed 25 Apr. 2015]. Sureda, A., Córdova, A., Ferrer, M., Pérez, G., Tur, J. and Pons, A. (2010). l-Citrulline-malate influence over branched chain amino acid utilization during exercise. Eur J Appl Physiol, 110(2), pp.341-351. Wax, B., Kavazis, A., Weldon, K. and Sperlak, J. (2015). Effects of Supplemental Citrulline Malate Ingestion During Repeated Bouts of Lower-Body Exercise in Advanced Weightlifters. Journal of Strength and Conditioning Research, 29(3), pp.786-792. World Anti-Doping Agency, (2014). Prohibited List. [online] Available at: https://www.wada- ama.org/en/resources/science-medicine/prohibited-list [Accessed 25 Apr. 2015].