Mechanisms of mechanical overload-induced skeletal muscle hypertrophy: current understanding and future directions

Michael D. Roberts, John J. McCarthy, Troy A. Hornberger, Stuart M. Phillips, Abigail L. Mackey, Gustavo A. Nader, Marni D. Boppart, Andreas N. Kavazis, Paul T. Reidy, Riki Ogasawara, Cleiton A. Libardi, Carlos Ugrinowitsch, Frank W. Booth, Karyn A. Esser

Research output: Contribution to journalReview articlepeer-review


Mechanisms underlying mechanical overload-induced skeletal muscle hypertrophy have been extensively researched since the landmark report by Morpurgo (1897) of "work-induced hypertrophy" in dogs that were treadmill trained. Much of the preclinical rodent and human resistance training research to date supports that involved mechanisms include enhanced mammalian/mechanistic target of rapamycin complex 1 (mTORC1) signaling, an expansion in translational capacity through ribosome biogenesis, increased satellite cell abundance and myonuclear accretion, and postexercise elevations in muscle protein synthesis rates. However, several lines of past and emerging evidence suggest that additional mechanisms that feed into or are independent of these processes are also involved. This review first provides a historical account of how mechanistic research into skeletal muscle hypertrophy has progressed. A comprehensive list of mechanisms associated with skeletal muscle hypertrophy is then outlined, and areas of disagreement involving these mechanisms are presented. Finally, future research directions involving many of the discussed mechanisms are proposed.

Original languageEnglish (US)
Pages (from-to)2679-2757
Number of pages79
JournalPhysiological Reviews
Issue number4
StatePublished - Oct 2023


  • hypertrophy
  • skeletal muscle
  • resistance training
  • myofiber
  • mechanical overload

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Physiology (medical)


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