Stimuli and sensors that initiate skeletal muscle hypertrophy following resistance exercise

J Appl Physiol (1985). 2019 Jan 1;126(1):30-43. doi: 10.1152/japplphysiol.00685.2018. Epub 2018 Oct 18.


One of the most striking adaptations to exercise is the skeletal muscle hypertrophy that occurs in response to resistance exercise. A large body of work shows that a mammalian target of rapamycin complex 1 (mTORC1)-mediated increase of muscle protein synthesis is the key, but not sole, mechanism by which resistance exercise causes muscle hypertrophy. While much of the hypertrophy signaling cascade has been identified, the initiating, resistance exercise-induced and hypertrophy-stimulating stimuli have remained elusive. For the purpose of this review, we define an initiating, resistance exercise-induced and hypertrophy-stimulating signal as "hypertrophy stimulus," and the sensor of such a signal as "hypertrophy sensor." In this review we discuss our current knowledge of specific mechanical stimuli, damage/injury-associated and metabolic stress-associated triggers, as potential hypertrophy stimuli. Mechanical signals are the prime hypertrophy stimuli candidates, and a filamin-C-BAG3-dependent regulation of mTORC1, Hippo, and autophagy signaling is a plausible albeit still incompletely characterized hypertrophy sensor. Other candidate mechanosensing mechanisms are nuclear deformation-initiated signaling or several mechanisms related to costameres, which are the functional equivalents of focal adhesions in other cells. While exercise-induced muscle damage is probably not essential for hypertrophy, it is still unclear whether and how such muscle damage could augment a hypertrophic response. Interventions that combine blood flow restriction and especially low load resistance exercise suggest that resistance exercise-regulated metabolites could be hypertrophy stimuli, but this is based on indirect evidence and metabolite candidates are poorly characterized.

Keywords: hypertrophy; mechanotransduction; signal transduction; skeletal muscle.

Publication types

  • Review

MeSH terms

  • Animals
  • Humans
  • Hypertrophy
  • Mechanotransduction, Cellular
  • Muscle, Skeletal / physiology*
  • Resistance Training*
  • Stress, Physiological
  • Weight-Bearing