Member Biography

Joshua Huot

Joshua Huot, Ph.D.

980 W. Walnut Street
R3 C547
Indianapolis, IN 46202
Phone: 317-278-4950

Research Program Membership

Associate member:

Assistant Professor
Department of Anatomy, Cell Biology, & Physiology
IU School of Medicine

Dr. Huot's research interests include:

My primary research interest is Cachexia, a multi-organ wasting syndrome affecting musculoskeletal health, and is directly responsible for worsened quality of life and survival in cancer patients and for over 30% of all cancer-related deaths. Though upwards of 80% of cancer patients experience cachexia, it remains an underserved research area, with no currently approved prevention or treatment options. When I began my postdoctoral fellowship as a musculoskeletal health enthusiast, it was my goal to better understand the mechanisms mediating musculoskeletal deficits in cancer patients. While it is my intention to continue this mission as an independent investigator, my postdoctoral fellowship has shown me that the cachexia field requires greater refinement in modeling human disease to better understand disease progression and ultimately identify therapeutic targets. As a result, aside from mechanistic research, much of my postdoctoral work has focused on generating translatable animal models which better mimic the clinical population. Throughout my postdoctoral training, I have spent considerable effort generating experimental models of advanced colorectal cancer (CRC) cachexia. The formation of liver metastases (LM), which occurs in roughly 70% of advanced CRC patients, is also highly associated with cachexia and worsened survival. Despite this, a vast majority of experimental models used for the study of cachexia do not incorporate metastatic disease, something that is particularly true of CRC, where subcutaneous (s.c.) tumor models are the preferred choice. To narrow this gap, I took a classical splenic injection approach to induce CRC tumor formation in the liver. Using this approach, I have demonstrated that CRC LM (C26, HCT116, MC38) exacerbates skeletal muscle wasting and weakness. Cachexia is often defined as muscle loss with or without fat loss. However, it is becoming clear that organ and tissue deficits caused by cancer and its treatments extend beyond skeletal muscle and fat. My initial work on CRC LM highlighted the importance of recognizing cachexia as a multi-organ wasting syndrome. It was previously shown that s.c. C26 tumor hosts did not present with bone loss, however I recently demonstrated that animals bearing C26 LM had marked trabecular bone loss, also in line with LM exacerbating cachexia. We also demonstrated bone loss in animals bearing MC38 and HCT116 LM. I have also expanded my multi-organ investigations, placing emphasis on cardiac dysfunction in settings of cachexia. We recently demonstrated cardiac abnormalities in animals treated with the multi-kinase inhibitors regorafenib and sorafenib, and in mice bearing CRC LM, as seen with patients suffering from cancer cachexia. My findings that formation of LM exacerbate cachexia in CRC has opened the door for me to investigate inter-tissue communication during disease progression. Although the mechanisms driving cancer cachexia have been studied for over thirty years, most research has focused on single organ perturbations, placing emphasis on tumor-tissue crosstalk and largely ignoring the role of inter-tissue communication. Aside from its role in sustaining whole body energy metabolism, the liver provides endocrine functions via its secreted cytokines (i.e., hepatokines). I plan to initiate a laboratory focused on how inter-tissue (e.g., liver-muscle) communication contributes to cancer and chemotherapy-induced cachexia. Moreover, as a certified strength and conditioning coach and exercise enthusiast, it is my ultimate goal to incorporate exercise as a therapeutic intervention to improve musculoskeletal health in cancer patients. Using established techniques of electromyography, I recently demonstrated that cancer and chemotherapy promote loss of motor unit connectivity (motor unit number estimation (MUNE)) in mice, which correlates with loss of muscle mass and weakness. Interestingly, reduced muscle force and MUNE persist one month following cessation of chemotherapy and/or following tumor resection, which may serve as a possible mechanism for persistent fatigue and muscle weakness reported in cancer patients. Interestingly, my recent data suggests that Adeno-associated virus (AAV)-mediated overexpression of optical atrophy 1 (OPA1) in the skeletal muscle preserves muscle force and MUNE in adult male mice (12-months) treated with the chemotherapy, cisplatin. Similarly, genetic overexpression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in skeletal muscle is protective against loss of muscle mass, muscle force, and MUNE in adult mice (18-months) treated with cisplatin. This data has led to a funded pilot grant through the IUSCCC (PI: Huot) aimed at mitochondrial targeting to restore MUNE and muscle function during cancer remission, specifically, following surgical tumor resection and cessation of chemotherapy (Study is underway). Continuing and building off my recently conducted projects, another foundation of my future research will make use of exercise interventions as a strategy to improve MUNE, muscle mass, and muscle function, during and following cancer and chemotherapy interventions.

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More Publications »

Post-doctoral Fellowship - Indiana University School of Medicine, Indianapolis, IN 2022

Ph.D. - University of North Carolina, Charlotte, NC 2018