Administration of a selective retinoic acid receptor-\u03b3 agonist improves neuromuscular strength in a rodent model of volumetric muscle loss

Michael E Whitely,Joseph C Wenke,Patrick B Collins,Masahiro Iwamoto

doi:10.1186/s40634-021-00378-3

Abstract

PurposeVolumetric muscle loss is a uniquely challenging pathology that results in irrecoverable functional deficits. Furthermore, a breakthrough drug or bioactive factor has yet to be established that adequately improves repair of these severe skeletal muscle injuries. This study sought to assess the ability of an orally administered selective retinoic acid receptor-γ agonist, palovarotene, to improve recovery of neuromuscular strength in a rat model of volumetric muscle loss.MethodsAn irrecoverable, full thickness defect was created in the tibialis anterior muscle of Lewis rats and animals were survived for 4 weeks. Functional recovery of the tibialis anterior muscle was assessed in vivo via neural stimulation and determination of peak isometric torque. Histological staining was performed to qualitatively assess fibrous scarring of the defect site.ResultsTreatment with the selective retinoic acid receptor-γ agonist, palovarotene, resulted in a 38% improvement of peak isometric torque in volumetric muscle loss affected limbs after 4 weeks of healing compared to untreated controls. Additionally, preliminary histological assessment suggests that oral administration of palovarotene reduced fibrous scarring at the defect site.ConclusionsThese results highlight the potential role of selective retinoic acid receptor-γ agonists in the design of regenerative medicine platforms to maximize skeletal muscle healing. Additional studies are needed to further elucidate cellular responses, optimize therapeutic delivery, and characterize synergistic potential with adjunct therapies.

Highlights

Skeletal muscle possesses a robust capacity to recover from injury, stemming from a population of resident progenitor cells who activate and fuse to repair damaged myofibers [10, 24, 50]
In vivo neuromuscular strength assessment Functional recovery of the tibialis anterior muscle was assessed in vivo via neural stimulation and determination of peak isometric torque 4 weeks after injury
A qualitative reduction in fibrous scarring was observed at the site of volumetric muscle loss (VML) in R667 treated animals, Fig. 2C

Summary

Introduction

Skeletal muscle possesses a robust capacity to recover from injury, stemming from a population of resident progenitor cells who activate and fuse to repair damaged myofibers [10, 24, 50]. The loss of progenitor cells and native extracellular matrix combine with an unrelenting immune response that promotes formation of nonfunctional fibrous tissue and severely inhibits de novo fiber regeneration [22, 32, 33]. The clinical standard of care remains surgical placement of muscle flaps followed by extensive rehabilitation [8]. Promising experimental platforms, such as minced muscle graft transplantation, improve muscle function and fiber regeneration, but have been unable to fully mitigate the pathological response and suffer from finite availability [1]. In contrast to other targets of tissue engineering, a breakthrough drug or bioactive factor has yet to be established that adequately promotes repair and regeneration of severe VML injuries. Development of a drug-based treatment that can be used in combination with current tissue engineering and regenerative rehabilitation programs to improve regenerative capacity and facilitate functional recovery would be invaluable

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