JNK regulates muscle remodeling via myostatin/SMAD inhibition

Authors: LESSARD, SARAH - Joslin Diabetes Center; MACDONALD, TARA - Joslin Diabetes Center; PATHAK, PRERANA - Joslin Diabetes Center; HAN, MYOUNG SOOK - University Of Massachusetts; COFFEY, VERNON - Bond University; EDGE, JOHANN - Massey University; RIVAS, DONATO - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; HIRSHMAN, MICHAEL - Joslin Diabetes Center; DAVIS, ROGER - University Of Massachusetts; GOODYEAR, LAURIE - Joslin Diabetes Center

Submitted to: Nature Communications
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/26/2018
Publication Date: 8/2/2018
Citation: Lessard, S.J., MacDonald, T.L., Pathak, P., Han, M., Coffey, V.G., Edge, J., Rivas, D.A., Hirshman, M.F., Davis, R.J., Goodyear, L.J. 2018. JNK regulates muscle remodeling via myostatin/SMAD inhibition. Nature Communications. 9:3030. https://doi.org/10.1038/s41467-018-05439-3.
DOI: https://doi.org/10.1038/s41467-018-05439-3

Interpretive Summary: Skeletal muscle has the ability to change and adapt in response to physical exercise. Endurance exercise, like running, stimulates improvements in muscle ability to burn fuel, while resistance exercise, like lifting weights, induces muscle growth. Here we show that the protein 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 stopped, an alternative program starts, resulting in smaller, more fuel burning muscle fibers, and enhanced aerobic fitness. When a muscle is exposed to mechanical stress, like a stretch, JNK starts muscle growth by turning on SMAD2, a protein that controls making specific growth genes, leading to inhibition of Myostatin, a protein that turns off muscle growth. In human skeletal muscle, this JNK/SMAD signaling axis is activated by a weight training exercise, but not a running exercise. We conclude that JNK has the ability to change skeletal muscle during exercise by regulating Myostatin/SMAD signaling.

Technical Abstract: 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) as 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 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.