Molecular Regulation of Exercise-Induced Muscle Fiber Hypertrophy

Abstract

Skeletal muscle hypertrophy is a widely sought exercise adaptation to counteract the muscle atrophy of aging and disease, or to improve athletic performance. While this desired muscle enlargement is a well-known adaptation to resistance exercise training (RT), the mechanistic underpinnings are not fully understood. The purpose of this review is thus to provide the reader with a summary of recent advances in molecular mechanisms-based on the most current literature-that are thought to promote RT-induced muscle hypertrophy. We have therefore focused this discussion on the following areas of fertile investigation: ribosomal function and biogenesis, muscle stem (satellite) cell activity, transcriptional regulation, mechanotransduction, and myokine signaling.

Figure 1.

Ribosomal function. Skeletal myofiber hypertrophy as an adaptation to resistance exercise training is accomplished by cellular protein accretion over time, which requires increased ribosomal function. Enhanced protein translation rates can be achieved by increased ribosomal efficiency (i.e., more translation per ribosome) and/or elevated ribosomal capacity via ribosome biogenesis (i.e., de novo synthesis of ribosomes). Current evidence indicates that both of these routes to enhanced translation are involved in resistance training hypertrophy, and support for the latter has been building rapidly in recent years.

Figure 2.

Distinguishing satellite cell–independent and –dependent myofiber hypertrophy. In smaller myofibers with small myonuclear domains (MNDs), resistance exercise training (RT)-induced cellular hypertrophy is not necessarily satellite cell–dependent and can be accomplished by protein accretion alone (via increased ribosomal efficiency and capacity), as each myonucleus has “room to expand” both its transcriptional activity and cytoplasmic domain. In contrast, in larger myofibers with MNDs at or approaching a ceiling size, additional nuclei are needed to support enhanced ribosomal function and biogenesis en route to protein accretion; thus, for successful RT-induced hypertrophy of fibers with larger MNDs, satellite cell–mediated myonuclear addition may be essential and rate-limiting. (From Adams and Bamman 2012; adapted, with permission.)

Figure 3.

Schematic of mechanosensing elements supported by recent evidence. The latest studies of molecules and communication networks localized to the extracellular matrix (ECM), sarcolemma, sarcoplasm, and sarcomere suggest the transduction of mechanosensing to hypertrophy signaling involves (1) increased phosphatidic acid (PA) via the mechanosensitive diacylglycerol kinase ζ (DGKz) and PA-induced mammalian target of rapamycin (mTOR) signaling, localized to late endosome–lysosomal (LEL) hybrid organelles; (2) signaling initiated by the mechanosensitive costamere complexes dystrophin-associated glycoprotein complex (DGC) and focal adhesion vinculin–talin–integrin complex; (3) signaling and nuclear transcriptional activity initiated by intermediate filaments (e.g., desmin, plectin-1); and (4) contraction-induced mobilization of muscle ankryn repeat proteins (MARPs) from titin filaments.