You are hereMarch 8, 2021 | Muscle Stem Cells
A New Target Identified in the Battle Against Age-related Muscle Loss
Review of “Inhibition of prostaglandin-degrading enzyme 15-PGDH rejuvenates aged muscle mass and strength” from Science by Stuart P. Atkinson
The loss of muscle function during aging, also known as sarcopenia, can significantly diminish the quality of life and increase morbidity and mortality [1, 2]; therefore, delineating the mechanisms controlling this detrimental process may provide novel therapeutic avenues. Previous research from the laboratory of Helen M. Blau (Stanford School of Medicine, Stanford, CA, USA) reported that Prostaglandin E2 (PGE2) stimulates muscle stem cells (MuSCs) in young mice and aids the regeneration of damaged muscle tissue , and now, the Blau team report the reduced expression of PGE2 and PGD2 and the increased expression of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a prostaglandin catabolizing protein, in aged human skeletal muscle tissue. Most excitingly, Palla et al. also provide evidence that supports 15-PGDH inhibition as a means to counteract the loss of muscle function observe during the aging process .
Analysis of aging muscle tissues in humans and mice highlighted elevated levels of 15-PGDH, which can degrade PGE2, and established that 15-PGDH expression in myofibers and interstitial macrophages within muscle prompts a reduction in PGE2 signaling, which significantly contributes to muscle atrophy in aged mice. Tellingly, the overexpression of 15-PGDH in young mice prompted the rapid and striking loss of muscle mass and strength, which strengthened the supposed link between this prostaglandin catabolizing protein, inhibited PGE2 signaling, and sarcopenia.
With this knowledge in mind, the authors evaluated the consequences of inhibiting 15-PGDH activity through a targeted genetic knockdown or the administration of a small molecule inhibitor. Encouragingly, they discovered that 15-PGDH inhibition countered muscle atrophy and prompted an increase in aged muscle mass, strength, and exercise performance. At the molecular level, 15-PGDH inhibition in aged mice prompted the physiological restoration of levels of PGE2 and signaling through PGE2 receptor 4 (EP4) to a “youthful” level, which subsequently augmented both mitochondrial biogenesis/function and autophagy and decreased transforming growth factor-beta signaling, which has been linked to muscle atrophy in aging , and ubiquitin-proteasome pathway function, suggesting that modulated proteolysis may attenuate muscle atrophy.
In summary, these findings suggest a role for PGE2 signaling in muscle atrophy and identify 15-PGDH as a promising therapeutic target to counteract the loss of muscle function during aging. The next steps in this exciting research include an investigation into whether 15-PGDH expression changes among different muscles and fiber types within muscles and the delineation of the mechanisms controlling the age-related increase in 15-PGDH levels. Regarding this latter research aim, the authors postulate a paracrine mechanism involving tissue-resident 15-PGDH-expressing macrophages.
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- Cohen S, Nathan JA, and Goldberg AL, Muscle wasting in disease: molecular mechanisms and promising therapies. Nature Reviews Drug Discovery 2015;14:58-74.
- Rolland Y, Czerwinski S, van Kan GA, et al., Sarcopenia: Its assessment, etiology, pathogenesis, consequences and future perspectives. The Journal of Nutrition Health and Aging 2008;12:433-450.
- Ho ATV, Palla AR, Blake MR, et al., Prostaglandin E2 is essential for efficacious skeletal muscle stem-cell function, augmenting regeneration and strength. Proceedings of the National Academy of Sciences 2017;114:6675.
- Palla AR, Ravichandran M, Wang YX, et al., Inhibition of prostaglandin-degrading enzyme 15-PGDH rejuvenates aged muscle mass and strength. Science 2021;371:eabc8059.
- Bonaldo P and Sandri M, Cellular and molecular mechanisms of muscle atrophy. Disease Models & Mechanisms 2013;6:25.