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Studies attributing gains in strength and lean body mass (LBM) to creatine monohydrate (CrM) during resistance exercise (RE) training have not assessed these changes alongside cellular and subcellular adaptations. Additionally, CrM-treated groups have seldom been compared with a group receiving a placebo similar in nitrogen and energy. The purpose of this study was to examine the effects of a CrM-containing protein-carbohydrate (PRO-CHO) supplement in comparison with a supplement containing a similar amount of nitrogen and energy on body composition, muscle strength, fiber-specific hypertrophy, and contractile protein accrual during RE training.In a double-blind, randomized protocol, resistance-trained males were matched for strength and placed into one of three groups: protein (PRO), PRO-CHO, or the same PRO-CHO supplement (1.5 g·kg−1 body weight·d−1) containing CrM (Cr-PRO-CHO) (0.1 g·kg−1 body weight·d−1). Assessments were completed the week before and after a 10-wk structured, supervised RE program: strength (1RM, three exercises), body composition (DEXA), and vastus lateralis muscle biopsies for determination of muscle fiber type (I, IIa, IIx), cross-sectional area (CSA), contractile protein, and creatine content.Cr-PRO-CHO provided greater improvements in 1RM strength. At least 40% of the strength improvements could be attributed to hypertrophy of muscle involved in this exercise. Cr-PRO-CHO also resulted in greater increases in LBM, fiber CSA, and contractile protein compared with PRO and PRO-CHO.In RE-trained participants, supplementation with Cr-PRO-CHO provided greater muscle hypertrophy than an equivalent dose of PRO-CHO, and this response was apparent at three levels of physiology (LBM, fiber CSA, and contractile protein content).