Inflammation and muscle wasting - NF-kB signaling and mir-31 regulate muscle function
Final Report Abstract
Setting out to investigate the association between ageing, inflammatory pathways muscle regeneration and muscle wasting, I looked at how increasing levels of certain proteins related to the NF-κB signaling pathway influence muscle function and muscle health. I had hypothesized that there is a “young” pathway and an “old” pathway, and that inducing the “young” pathway in older individuals would protect their muscles from injury and wasting. However, using electroporation – that is injecting DNA into the muscle and then making the muscle fibers permeable by applying electric current – to raise the protein levels caused injury and remodeling in the muscles. Changing the protocol to allow for healing and looking at a more chronic response to changes in NF-κB signaling did not yield results that were congruent with our hypothesis. At the same time, I joined another project that modeled a rat after a patient with a rare genetic muscle disease. We created the first rat model for desminopathy, a disease associated with muscle weakness, muscle wasting and heart disease. To date, there is no treatment available for desminopathy. We investigated this new rat model to look at changes to the skeletal muscle in ageing as well as acute and chronic exercise, and examined the heart phenotype. While we saw differences in our mutated rats and their healthy littermates at any age and irrespective of exercise, we were particularly interested in how mechanical stress through physical activity can exacerbate disease progression. In the end, we concluded that our desminopathy rat model has enough similarities with the human disease to next investigate therapeutic strategies. I have secured funding to transfer the rat model to Germany and start exploring the effect of promising drugs that might slow disease progression in desminopathy.
Publications
- “Generation of desminopathy in rats using CRISPR‐Cas9.” Journal of Cachexia, Sarcopenia and Muscle, 2020
Henning T. Langer, Agata A. Mossakowski, Brandon J. Willis, Kristin N. Grimsrud, Joshua A. Wood, Kevin C.K. Lloyd, Hermann Zbinden‐Foncea, Keith Baar
(See online at https://doi.org/10.1002/jcsm.12619) - “A mutation in desmin makes skeletal muscle less vulnerable to acute muscle damage after eccentric loading in rats.” FASEB, 2021
Henning T. Langer, Agata A. Mossakowski, Alec M. Avey, Ross P. Wohlgemuth, Lucas R. Smith, Hermann Zbinden‐Foncea, Keith Baar
(See online at https://doi.org/10.1096/fj.202100711rr) - “Cannabidiol Does Not Impair Anabolic Signaling Following Eccentric Contractions in Rats.” Int J Sport Nutr Exerc Metab, 2021
Henning T. Langer, Agata A. Mossakowski, Suraj Pathak, Marc Mascal, Keith Baar
(See online at https://doi.org/10.1123/ijsnem.2020-0270)
