JNK regulates muscle remodeling via myostatin/SMAD inhibition

• Published in: Nature communications Vol. 9; no. 1; pp. 3030 - 14
• Main Authors: Lessard, Sarah J., MacDonald, Tara L., Pathak, Prerana, Han, Myoung Sook, Coffey, Vernon G., Edge, Johann, Rivas, Donato A., Hirshman, Michael F., Davis, Roger J., Goodyear, Laurie J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.08.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 13/106; 13/109; 13/95; 14; 14/34; 14/63; 38; 38/77; 631/80/86; 692/698/1671/1668; Adult; Animals; c-Jun protein; Cardiorespiratory fitness; Cell Nucleus - metabolism; Durability; Endurance; Enzyme Activation; Exercise; Fitness; Gene Expression Regulation; HEK293 Cells; Humanities and Social Sciences; Humans; Hypertrophy; Integrases - metabolism; JNK Mitogen-Activated Protein Kinases - metabolism; JNK protein; Mice, Inbred C57BL; Mice, Knockout; Molecular machines; multidisciplinary; Muscle Development; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscles; Muscles - metabolism; Musculoskeletal system; Myostatin; Myostatin - metabolism; Oxidation resistance; Phosphorylation; Physical Conditioning, Animal; Physical Endurance; Physical exercise; Protein Transport; Science; Science (multidisciplinary); Signal Transduction; Signaling; Skeletal muscle; Smad protein; Smad Proteins - antagonists & inhibitors; Smad Proteins - metabolism; Smad2 protein; Transcription factors
• ISSN: 2041-1723; 2041-1723
• 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. Endurance and resistance exercise have different effects on skeletal muscle phenotype. Using mouse models and human subjects, the authors show that JNK/Smad2 signaling acts as molecular switch that when activated by resistance exercise leads to hypertrophy, and when inhibited promotes endurance adaptations in muscle.