Multiscale analysis of a regenerative therapy for treatment of volumetric muscle loss injury

Carlos A Aguilar,Chelsea Peragallo,Sarah M Greising,Jacqueline Larouche,Stephen M Goldman,Alain Watts,Benjamin T Corona,Christina Zook

doi:10.1038/s41420-018-0027-8

Abstract

Skeletal muscle possesses a remarkable capacity to regenerate when injured, but when confronted with major traumatic injury resulting in volumetric muscle loss (VML), the regenerative process consistently fails. The loss of muscle tissue and function from VML injury has prompted development of a suite of therapeutic approaches but these strategies have proceeded without a comprehensive understanding of the molecular landscape that drives the injury response. Herein, we administered a VML injury in an established rodent model and monitored the evolution of the healing phenomenology over multiple time points using muscle function testing, histology, and expression profiling by RNA sequencing. The injury response was then compared to a regenerative medicine treatment using orthotopic transplantation of autologous minced muscle grafts (~1 mm3 tissue fragments). A chronic inflammatory and fibrotic response was observed at all time points following VML. These results suggest that the pathological response to VML injury during the acute stage of the healing response overwhelms endogenous and therapeutic regenerative processes. Overall, the data presented delineate key molecular characteristics of the pathobiological response to VML injury that are critical effectors of effective regenerative treatment paradigms.

Highlights

Skeletal muscle comprises over 40% of body mass in lean individuals, is primarily responsible for coordinating voluntary movements and can readily adapt to its environment
Currently, very little is known about the global molecular response after volumetric muscle loss (VML) and why this injury exceeds skeletal muscle’s endogenous regenerative capabilities through satellite cells
Understanding the molecular signals that induce the response of skeletal muscle to adopt a non-regenerative phenotype and when these signals are presented is paramount in advancing our understanding of VML pathogenesis and therapeutic efficacy

Summary

Introduction

Skeletal muscle comprises over 40% of body mass in lean individuals, is primarily responsible for coordinating voluntary movements and can readily adapt to its environment. After volumetric muscle loss (VML) injury[2], which is a type of severe trauma that ablates resident cells and structures primarily responsible for regeneration, the intrinsic muscle regenerative process fails[3]. VML is a common clinical outcome after open or closed (e.g., crush injury requiring fasciotomy and tissue evacuation) extremity trauma, for which there are currently no regenerative standards of care. The magnitude and location of VML injuries result in considerable heterogeneity and necessitate a cadre of therapies. A small VML defect isolated to a peripheral portion of a muscle unit may be best compensated by synergist hypertrophy mediated through physical therapy. Massive VML defects have been shown to not respond to conventional physical therapy and may require regenerative medicine augmentation. Regenerative treatments for VML have utilized various strategies[6,7,8,9,10,11,12,13,14] but require significant further advancement to be of therapeutic benefit to patients presenting acute or chronic VML injury

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