5% Strength: Lumacaftor concentration PL=0-6.7 % vs. HMB +15.7 % – 23.5 % Ransone 2003[24] College football players Progressive resistance and endurance exercise No No 4 weeks, 3 grams per day HMB-Ca No Skin Folds Bench Press, Power Cleans, Squats 1-RM FFM: +0.3 FM: – 3.8 Strength: 1.7 % increase Kreider 2000 [18] Trained, college football players Offseason strength and conditioning program Yes No 4 weeks, 3 grams per day HMB-Ca No DXA Bench Press, Power Cleans, Squats 1-RM, 12×6 second sprint performance No Effects O’Connor 2007[25] Trained rugby players, 25 yrs of age Progressive resistance training No No 6 weeks, 3 grams of HMB-Ca or HMB-Ca + Creatine per day 3 grams creatine

per day Skin Folds Squat, Bench Press, and Deadlift 1-RM Wingate Power Neither HMB-Ca nor creatine had an effect Slater 2001[26] College-aged, trained polo players and rowers Non-controlled workouts assigned by the athletes’ respective coaches Unknown No 6 weeks, 3 grams per day HMB-Ca No DA Bench Press, Hip Sled, Pullups 3-RM No significant effects * Abbreviations used in the table. TOBEC-total-body electrical conductivity; DXA-Dual-energy x-ray Decitabine ic50 absorptiometry; BIA-bioelectrical impedance; FFM-fat free mass; FM-fat mass; LBM-lean body mass (TOBEC). HMB metabolism, pharmacokinetics and retention Metabolism HMB is naturally produced

in animals and humans from the amino acid leucine [27]. The first step in production of HMB is the reversible transamination of leucine to α-keto-isocaproate (KIC) by the enzyme branched chain amino acid transferase [28] (Figure 1). After leucine is metabolized to KIC, KIC is either metabolized into isovaleryl-CoA by the enzymeα-ketoacid dehydrogenase in the mitochondria, or into HMB in the cytosol,

by the enzymeα-ketoisocaproate dioxygenase [28]. KIC is primarily metabolized into isovaleryl-CoA, with only approximately 5% of leucine being converted into HMB [28]. To put this into perspective, an individual would need to consume over 600 g of high quality protein to obtain the amount of leucine (60 grams) necessary to produce the typical 3 g daily dosage of HMB used in human studies [9]. Since consumption of this amount of protein is impractical, HMB is typically increased via dietary supplementation. Figure 1 The metabolism of beta-hyroxy-beta-methyl-butyrate. Rate of appearance and retention between varying forms of HMB As a dietary supplement, HMB has been commercially available PAK6 as a mono-hydrated calcium salt, with the empirical formula Ca (HMB)2-H2O (HMB-Ca). The magnitude and rate of appearance of HMB following ingestion is dependent on the dose, and whether or not it is consumed with additional nutrients. Specifically, Vukovich et al. [29] found that 1 g of HMB-Ca resulted in a peak HMB level in blood two hours following ingestion, while 3 g resulted in peak HMB levels 60 minutes after ingestion at 300% greater plasma concentrations (487 vs. 120 nmol·ml-1), and greater losses in urine (28% vs. 14%), for 3 and 1 g HMB-Ca ingestion, respectively.