Muscle Fibrosis in Cachexia - Project summary Cachexia is a muscle-wasting syndrome that affects half of all cancer patients and a quarter of all patients with chronic diseases. Scientifically, cachexia is defined by muscle loss in parallel to systemic inflammation (e.g. IL- 6 signaling). Cachexia exists on a spectrum that leads to progressive functional decline and a refractory end- stage. Refractory cachexia is not responsive to primary treatment, anti-inflammatory therapies, or exercise, which are effective in earlier phases. The key regulators of the transition to the refractory phase of cachexia are unknown. Sustained inflammation leads to tissue extracellular matrix (ECM) remodeling and fibrosis. In muscle, the ECM regulates muscle physiology and function, which can become disrupted in disease. While muscle fibrosis is linked to increased mortality in cancer patients, the relationship between ECM and refractory cachexia is unknown. Since current preclinical models of cachexia are not designed to distinguish early and refractory phase biology, we developed a new mouse model with an extended lifespan, expanding the opportunity to probe early and refractory phase cachexia phenomena. The scientific goal of this application is to determine whether muscle fibrosis is a barrier to responsiveness to therapy in refractory cachexia in our novel model. Aim 1 investigates the individual and combine effects of anti-IL-6 and anti-fibrosis treatments at early and refractory stages of cachexia on muscle mechanics, function, wasting, and survival. We hypothesize that dual treatment with anti-inflammatories and anti-fibrotic will rehabilitate the cachexia phenotype at previously refractory stages. Aim 2 directly examines the role of cachexia related fibrosis in response to exercise. We hypothesize that anti- fibrotic therapies will improve the efficacy of both endurance and resistance exercises during the refractory cachexia. These studies will expand our knowledge of the biology of refractory cachexia, broaden our understanding of the role of ECM in cachexia, and initiate preclinical evaluation of synergistic therapies. This is an application for a K08 Career Development Award for Ishan Roy, MD, PhD, Physician Scientist at Shirley Ryan AbilityLab (SRAlab) and Assistant Professor at the Department of Physical Medicine and Rehabilitation at Northwestern University (NU). The career goal of this application is for Dr. Roy to gain expertise in the fields of muscle physiology, exercise science, and ECM biology. Combined with his prior background in immunology and cancer biology, Dr. Roy will then apply his new training to the field of cachexia biology. Richard Lieber, PhD is the primary mentor and an expert in muscle physiology and rehabilitation. G.R. Scott Budinger, MD is co-mentor and an expert in inflammation and tissue fibrosis. Both SRAlab and NU have made a significant commitment to Dr. Roy’s career development and this application represents the next step in establishing a mentorship and training plan to achieve Dr. Roy’s career goal of independence.
