We have two main interests in the lab. First, we want to understand the relationship between neuroinflammation and debilitating muscle fatigue. Our ongoing studies suggest many neural stressors, including infections, chronic diseases and even aging , induce brain-muscle crosstalk via the circulation that disrupts energy production in muscle. Second, we are interested in identifying long range signals that promote muscle regeneration. By performing scSeq of an entire organism during muscle repair, we have identified many candidate ligands that are expressed far from the muscle stem cell niche. Our ongoing studies are validating these candidates using high throughout gene expression and gene knockout approaches.
Neuroinflammation and inter-organ communication
We recently found infectious diseases, including bacterial and viral infections, and chronic diseases, such as Alzheimer’s disease, activate a brain to muscle communication pathway. The brain-muscle signaling axis changes energy production in muscle, which may be important to shift the energy balance away from muscle and toward the nervous system and the immune system to promote disease recovery. We are now using proteomics approaches to identify proteins that are made in the nervous system and subsequently translocate to skeletal muscle to regulate muscle function.
In response to infection or chronic disease, reactive oxygen species (ROS) activate expression of the cytokine Upd3 (in flies) or IL-6 (in mice). The cytokines enter circulation, translocate to skeletal muscle, and activate the JAK/Stat pathway. JAK/Stat signaling in muscle reduces mitochondrial activity, which inhibits muscle performance.
Infection and chronic disease activate a systemic brain-muscle signaling axis
S Yang*, M Tian*, Y Dai, R Wang, S Yamada, S Feng, Y Wang, D Chhangani, T Ou, W Li, X Guo, J McAdow, DE Rincon-Limas, X Yin, W Tai, G Cheng, AN Johnson, Sci Immunol 2024 July
Current projects on inter-organ communication
- Brain-muscle communication in infectious disease
- Brain-muscle communication in chronic disease
- Brain-muscle communication in aging
- Exercise as a treatment for Alzheimer’s disease
Long range signaling in muscle regeneration
Skeletal muscle is one of the most regenerative organs in vertebrates, that uses well defined stem cells to repair and replaced damaged muscle cells. We are interested in understanding how long-range signals communicate with muscle stem cells to direct the regenerative response. Our zebrafish model of muscle injury can be used for single cell sequencing an entire organism to identify long-range signals that are activated during muscle regeneration. Once validated in zebrafish, we can test candidate molecules to repair injured muscles in a mammalian model of muscle regeneration. This approach is uncovering many genes not previously known to regulate regeneration.
Current projects on muscle regeneration
- Epidermis-muscle stem cell communication
- Brain-muscle stem cell communication
- Repair programs of systemic versus local injury
Manuscript coming soon to biorxiv!!!
H Dean*, V Saraswathy*, A. Saini, R. Kheireddine, T. Ou, J. McAdow, A. Tendolkar, MH Mokalled, AN Johnson
Genetic Disease
We are collaborating with clinicians at Washington University to identify new genes and variants associated with inherited diseases. One focus of the lab is characterizing muscle diseases known as myopathies using zebrafish. Our in vivo approach allows us to understand how all parts of the musculoskeletal system are affected by and contribute to muscle disease. A second focus of the lab is to use Drosophila as a primary screening platform to understand if gene and variants identified in local patients are causative of a wide array of conditions including structural birth defects and neurological diseases. Our screening approach is aimed at assisting with the clinical diagnosis of patients with genetic disease.
