JNK regulates muscle remodeling via myostatin/SMAD inhibition

Nat Commun. 2018 Aug 2;9(1):3030. doi: 10.1038/s41467-018-05439-3.


Skeletal muscle has a remarkable plasticity to adapt and remodel in response to environmental cues, such as physical exercise. Endurance exercise stimulates improvements in muscle oxidative capacity, while resistance exercise induces muscle growth. Here we show that the c-Jun N-terminal kinase (JNK) is a molecular switch that when active, stimulates muscle fibers to grow, resulting in increased muscle mass. Conversely, when muscle JNK activation is suppressed, an alternative remodeling program is initiated, resulting in smaller, more oxidative muscle fibers, and enhanced aerobic fitness. When muscle is exposed to mechanical stress, JNK initiates muscle growth via phosphorylation of the transcription factor, SMAD2, at specific linker region residues leading to inhibition of the growth suppressor, myostatin. In human skeletal muscle, this JNK/SMAD signaling axis is activated by resistance exercise, but not endurance exercise. We conclude that JNK acts as a key mediator of muscle remodeling during exercise via regulation of myostatin/SMAD signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Cell Nucleus / metabolism
  • Enzyme Activation
  • Gene Expression Regulation
  • HEK293 Cells
  • Humans
  • Hypertrophy
  • Integrases / metabolism
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle Development
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Muscles / metabolism*
  • Myostatin / metabolism*
  • Phosphorylation
  • Physical Conditioning, Animal
  • Physical Endurance
  • Protein Transport
  • Signal Transduction
  • Smad Proteins / antagonists & inhibitors
  • Smad Proteins / metabolism*


  • Myostatin
  • Smad Proteins
  • JNK Mitogen-Activated Protein Kinases
  • Cre recombinase
  • Integrases