Cellular and Molecular Determinants of Post-Burn Myopathy

ABSTRACT Severe burn trauma triggers profound muscle atrophy and weakness which persists for years post- injury. To date, research efforts have predominantly explored hypermetabolic and catabolic signaling within muscle cells resulting from burn injuries, with limited attention to other contributing factors.. The intricate processes of

muscle regeneration and remodeling involve multiple cell types within the muscle niche, including fibroblasts and immune cells. We propose that burn injuries disrupt crucial cell-to-cell signaling pathways, resulting in muscle dysfunction that cannot be solely attributed to hypermetabolism. We are uniquely positioned to pursue

our long-term goal of unveiling cellular and molecular drivers of burn-induced myopathy with the aim of identifying innovative therapeutic targets that preserve muscle size and function. Over the next five years, we will pursue four interconnected yet distinct projects. Project 1 will identify cellular determinants of muscle

fibrosis after severe burn injury. Recent findings indicate significant collagen deposition post-murine burn injury, indicative of unresolved fibrosis which may increase tissue stiffness and reduce strength. We will employ a comprehensive multi-omic (transcriptomic and proteomic) approach to unveil cellular and molecular

determinants of burn-induced fibrosis. Identified pathological mediators will be studied through transgenic and pharmacological interventions. Various techniques will assess collagen dynamics, including architecture, orientation, and cross-linking, to comprehend ECM remodeling potential post-burn injury. Project 2 will

determine the impact of burn injury on immune cell function and its consequence on muscle wasting and weakness. We will assess immune cell abundance and phenotype in muscle in the days to months following burn injury. Additionally, we will investigate how burn injury epigenetically, metabolically, and

functionally reprograms immune cells. Upon identification of cellular perpetuators of muscle dysfunction after burn, we may pursue cell depletion strategies to directly examine their role. Project 3 will elucidate effect of immunomodulation on muscle physiology after burn injury. We will explore whether modifying

macrophage phenotype using Toll-like receptor (TLR) agonists can promote healthy ECM turnover and improves muscle mechanics and strength. Project 4 will fill the knowledge gap regarding the role of muscle MyD88 in burn-induced cachexia and muscle regeneration. MyD88, a TLR adaptor molecule expressed in

muscle, has been implicated in cancer cachexia, yet it is also required for myofiber regeneration. We will employ a skeletal muscle MyD88 knockout transgenic animal to determine whether MyD88 exerts a pro- restorative or pro-wasting effect following burn injury. These projects collectively support our overarching aim:

to enhance our understanding of burn-induced cellular and molecular dysfunction which will identify novel therapeutic targets for improving muscle function in patients after severe burn injury.