Review Ger J Exerc Sport Res https://doi.org/10.1007/s12662-020-00652-z Received: 13 October 2019 Accepted: 19 March 2020 © Springer-Verlag GmbH Deutschland, ein Teil von Springer Nature 2020 Victor Hugo F. Arantes 1 · Dailson Paulucio da Silva 1 · Renato Luiz de Alvarenga 1 · Augusto Terra 1 · Alexander Koch 2 · Marco Machado 3 · Fernando Augusto Monteiro Saboia Pompeu 1 1 Biometry Laboratory, School of Physical Education and Sports, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil 2 Exercise Physiology Laboratory, Lenoir-Rhyne University, Hickory, USA 3 Laboratory of Physiology and Biokinetics, UNIG Campus V, Itaperuna, Rio de Janeiro, Brazil Skeletal muscle hypertrophy: molecular and applied aspects of exercise physiology Introduction Skeletal muscle hypertrophyoccurs when the net protein balance is positive, in other words, when protein synthesis is higher than degradation. Te theory of musculoskeletal growth based on an endogenous acute rise in hormonal cir- culation caused by resistance exercise (Kraemer & Ratamess, 2005) was sup- ported for years. However, advances in molecular biology have revolutionized the understanding of the hypertrophic process and an approach based on three primary factors (mechanical tension, muscle damage and, to a lesser ex- tent, metabolic stress) was hypothesized (Schoenfeld, 2010). Te protein syn- thesis necessary for the maintenance of a positive protein balance is regulated by many mechanisms and is divided into two phases: transcription and transla- tion. Te first occurs inside the cell nucleus and stimulates the creation of messenger Ribonucleic Acid (mRNA) from a Deoxyribonucleic Acid (DNA) strand, while the second occurs in the cytoplasm and represents the reading of genetic information for the formation of new proteins. Several enzymatic cascades serve as pathways for protein synthesis. Stud- ies observed that mechanistic target of rapamycin (mTOR) plays a central role (Goodman et al., 2011) in promoting pro- tein synthesis, since its inhibition is able to slow down or block other anabolic kinases (Drummond et al., 2009) and prevent skeletal muscle hypertrophy (Bo- dine et al., 2001). In addition, exercise- induced activation of a downstream, p70 ribosomal protein S6 kinase (p70S6K) is highly correlated to skeletal muscle gain due to resistance training (Baar & Esser, 1999; Terzis et al., 2008). In contrast to the model proposed by the hormonal theory, acute elevation of anabolic hor- mone serum concentrations (growthhor- mone, insulin-like growth factor 1, and testosterone) caused by resistance exer- cise/training is not significantly corre- lated to skeletal muscle growth (West & Phillips, 2012; Mitchell et al., 2013), and, also, it is not considered a decisive factor for skeletal muscle growth (West et al., 2010). Moreover, the intracellular avail- ability (Beugnet, Tee, Taylor, & Proud, 2003) of amino acids stimulates protein synthesis through mTOR (Dickinson et al., 2011) and, at the same time, natu- ral compounds (ursolic acid and toma- tidine) activate anabolic kinases and in- hibit other pathways, blocking anabolism (Kunkel et al., 2011; Figueiredo & Nader, 2012; Dyle et al., 2014) and opening a gap to amino acid supplementation to pro- vide the anabolic effect of the resistance exercise (Karlsson et al., 2004; Blom- strand, Eliasson, Karlsson, & Köhnke, 2006; Dreyer et al., 2008). Resistance training-induced hyper- trophy is more easily attributable to intrinsic muscle factors than to systemic factors (Mitchell et al., 2013). How- ever, since p70S6K phosphorylation is greater in fast-twitch fibers (Koopman, Zorenc, Gransier, Cameron-Smith, & Loon, 2006; Tannerstedt, Apro, & Blom- strand, 2009), genetic factors such as the dominant muscle fiber type must also be considered. Tus, individuals or muscle groups with a greater amount of type II fibers likely have greater potential for hypertrophy (Haun et al., 2019). In view of the fact that the latest published guidelines for resistance training (Amer- ican College of Sports, 2009) have not been updated according to literature, there is a need for a consideration of the newer research findings when making practical recommendations. Hence, the aims of this review are to highlight the role of anabolic intracellular signaling pathways in exercise-derived anabolism/ hypertrophy and demonstrate its ap- plicability in resistance training, taking into account: (a) intensity; (b) volume; (c) rest interval; (d) types of contraction; (e) velocity of contraction; (f) exercise order; and (g) frequency. Methods Literature search A literature search was conducted in the PubMed database from 1995 to Novem- ber 2019 focusing on the effects of resis- tance training on skeletal muscle hyper- trophy. Te following terms were use in the search: “skeletal muscle protein syn- German Journal of Exercise and Sport Research