Myostatin inhibition and upregulation of the myostatin inhibitor follistatin are approaches to spurring increased muscle growth. This class of approach has been shown to work in humans to at least some degree, and there are numerous heavily muscled myostatin loss of function mutants in various animal species, both naturally occurring and created via genetic technologies. SMAD2 is a related regulatory protein, and some efforts to increase muscle growth have targeted it. Further exploration in this same cluster of regulatory proteins leads to JNK, the subject of today's open access paper.
This portion of mammalian biochemistry is an area of interest to researchers as a potential means to treat sarcopenia, the characteristic loss of muscle mass and strength that occurs with aging. If muscle growth can be dialed up as needed, something that seems a plausible goal at this point, then that capability would deal with half of the problem of sarcopenia, leaving just the quality of the muscle to be addressed. It might also be deployed as a compensatory therapy for forms of muscle wasting, such as that occurring as a result of cancer and its treatment. Of course, one suspects that use by younger people as an enhancement therapy would eventually become just as widespread. Who wouldn't want a little extra muscle without having to put in the effort to gain it?
It remains to be seen which of the variety of efforts to manipulate the regulation of muscle growth ultimately succeed in reaching clinical application. The established forms of treatment, such as follistatin gene therapy or myostatin antibodies, are conceptually simple enough. The question is more one of when gene and antibody therapies in general pass the point of cost and reliability that leads to widespread availability via medical tourism, as occurred for early stem cell therapies nearly twenty years ago. Now is about when it should start to happen, given the state of the science for delivery or upregulation of proteins.
The adaptation of muscle to endurance or resistance exercise is a highly variable trait in humans and animals. As a means to discover the molecular mechanisms that regulate endurance adaptations in skeletal muscle, our previous work utilized rodent models generated by selective breeding for low- or high-adaptive response to endurance exercise. The failure to improve aerobic capacity in low responders to endurance training occurred in conjunction with a less oxidative muscle phenotype and deficiencies in exercise-induced angiogenesis in skeletal muscle. Importantly, blunted endurance remodeling in the skeletal muscle of low responders to endurance exercise was associated with increased risk for chronic metabolic disease. Our data demonstrated that hyper-activation of the mitogen-activated protein kinase, c-Jun N-terminal kinase (JNK), was associated with the failure of muscle to undergo endurance remodeling with exercise. Thus, we hypothesized that JNK activation during exercise is a negative regulator of endurance adaptations in muscle.
The present investigation aimed to directly test the hypothesis that JNK is a critical mediator of muscle remodeling. We employed a multi-disciplinary approach to determine the effect of JNK hyper-activation and loss of function on muscle phenotype and remodeling, including tissue culture systems, animal models, and human subjects. This work identifies JNK as a molecular switch that, when active, stimulates muscle fibers to grow, leading to increased muscle mass. Conversely, when JNK is inhibited, an alternative adaptive program is induced, leading to endurance adaptations and enhanced aerobic capacity.
We find that JNK exerts its effects on muscle phenotype via phosphorylation of the transcription factor, SMAD2, at specific linker-region residues. JNK-mediated SMAD2 phosphorylation results in negative regulation of the myostatin/TGFβ pathway, thus allowing for muscle growth. In addition, we demonstrate that in human skeletal muscle, this JNK/SMAD signaling axis is activated by resistance exercise, but not endurance exercise, therefore identifying JNK/SMAD signaling as a target to induce muscle remodeling. These data enhance our understanding of the fundamental mechanisms that mediate muscle reprogramming and remodeling in vivo.