Immunotargeting and Metabolic Therapeutic Strategies to Improve Muscle Recovery After Severe Trauma

Relevance of the Project to at Least One FY20 PRMRP Topic Area: This project addresses the needs outlined in the Areas of Encouragement 'research to better understand tissue-specific diseases or injuries with a focus on treatment, recovery or regeneration.'

Patients This Proposal Will Help: Severe muscle injuries stemming from lower-limb extremity trauma are an enormous medical problem ($400B/year ascribed to trauma in the U.S.) and significantly impacts DoD readiness and performance (>24M limited duty days in 2005). The debilitating consequences of severe muscle injuries from lower-limb extremity trauma have been shown to result in pronounced and permanent disabilities ranging from declines in limb function, to development of osteoarthritic pathology and delayed or elected limb amputation.

Potential Clinical Applications, Benefits, and Risks: We plan to address the key barriers to improved clinical treatment of VML through: 1) tuning the immune system to minimize fibrosis and maximize tissue regeneration and 2) manipulation of metabolism to improve the regenerative activities of endogenous and transplanted stem cells that repair muscle tissue and restore muscle function.

While efforts to develop treatments that hasten and improve healing for lower-limb skeletal muscle injuries are ongoing, none have worked for volumetric muscle loss (VML). Regenerative approaches still suffer from the inhibitive and fibrotic microenvironment induced by the VML injury. This is because VML-injured tissues are overwhelmed by persistent inflammation that drives excessive collagen deposition and fibrosis, which in turn hinders repair from endogenous or transplanted stem cells. A successful therapy for VML would both remove the pathological response (fibrosis) and provide functional recovery through muscle regeneration. Currently, no effective therapies have been translated to the clinic for VML, and new regenerative methods are urgently needed. The lack of successful therapies for VML may be driven by the lack of available nutrients to support regeneration, but how energy usage (metabolism) changes from VML affect the activity of endogenous and transplanted muscle progenitors remains unknown.

Herein, we will use readily translatable therapeutic strategies to restore muscle function after VML that mitigate macrophage-induced fibrosis (Aim 1) and restore metabolic signaling needed to enact muscle regeneration (Aim 2). The first aim of this project will explore genetic and pharmacological manipulation of fibrogenic signaling to reduce fibrotic scarring and create a supportive environment for subsequent therapy. The second aim of this proposal will evaluate metabolic repletion to restore the regenerative activity of endogenous muscle stem cells and transplanted muscle fibers. These studies will provide both mechanistic insights into the drivers of the VML response as well as how different treatment strategies can be combined to enhance muscle regeneration, which will create new personalized regenerative medicine programs to treat VML. This information can be used by medical personnel to understand recovery, track treatment efficacy, and inhibit fibrotic scarring that drives subsequent pathologies for Service Members. The approaches we will investigate have been approved and are on track to be approved by the FDA, minimizing risk and facilitating clinical translation. Successful completion of this study possesses enormous potential to save and improve the lives of Wounded Warriors and galvanize precision care of musculoskeletal trauma to reduce the medical cost and loss associated with recovery.

Projected Timeline/Expected Patient-Related Outcomes: We will rapidly deploy our treatment interventions. In the first 24 months, we will demonstrate the ability of our immune modulating treatments to prevent fibrosis and optimize our metabolic repletion approach using our mouse VML model. From months 18-36, we will also validate our metabolic therapies to improve the efficacy of transplantation of autologous muscle fibers.

Applicability and Impact to Service Members, Veterans, and/or Their Family Members: This proposed research will significantly improve current treatment strategies available to all patients who are at risk of developing muscle fibrosis. Through this proposal, we will improve our understanding of fibrosis and VML and provide novel interventions to prevent these debilitating processes in Service Members, Veterans, and civilians. We foresee these therapies being deployed to units where prolonged field care may be required as well as to military and civilian hospitals and clinics to treat high-risk patients early after their trauma or surgery to prevent fibrosis and permanent disability.