Gene expression profiling of skeletal muscle after volumetric muscle loss

Abstract

Volumetric muscle loss (VML), usually occurring following traumatic injury, results in a composite loss of muscle mass. These injuries manifest as decreased strength and functional impairments. Clinically, these injuries often heal with fibrosis, as opposed to skeletal muscle regeneration. This study examines the healing patterns of a skeletal muscle following VML in a murine model. Eight-week old male C57BL/6J mice used in the study underwent either bilateral VML injury or cryoinjury, a widely used model known to induce skeletal muscle regeneration. Skeletal muscle was harvested at 2 and 4 weeks following injury and subjected to histological analysis. H&E staining demonstrated skeletal muscle regeneration following cryoinjury, but not VML, at either timepoint post-injury. Additionally, samples were analyzed using a wound-healing PCR array to identify differentially regulated genes of interest in VML and cryoinjury, as compared to noninjured controls. The gene array data further demonstrated prolonged inflammation and increased pro-fibrotic activity in the VML injured muscles, as compared to cryoinjury. In addition, IGF1, a known myogenic factor, was significantly decreased following VML, as compared to cryoinjury, in both ELISA and PCR. This study offers an insight into the pathophysiology of VML injury and reveals a gene profile of a nonregenerating skeletal muscle.

The effect of autologous repair and voluntary wheel running on force recovery in a rat model of volumetric muscle loss

“…coordination of the inflammatory response, fibrotic response and myogenesis for optimal growth and repair. Chronic inflammation is associated with VML (Nuutila et al, 2017) and increased gene expression of inflammatory modulators have been reported at various time points following VML (Corona et al 2018). Our laboratory has demonstrated elevated expression of inflammatory cytokines TGF-β and interleukin (IL)-1β following VML (Kim et al, 2020).…”

“…Skeletal muscle regeneration is a process that is highly regulated and involves coordination of the inflammatory response, fibrotic response and myogenesis for optimal growth and repair. Chronic inflammation is associated with VML (Nuutila et al., 2017) and increased gene expression of inflammatory modulators have been reported at various time points following VML (Corona et al. 2018).…”

In Vivo Printing of Nanoenabled Scaffolds for the Treatment of Skeletal Muscle Injuries

“…[2] However, when a large proportion of mass is lost within a given muscle, as the result of a trauma, disease, or surgical ablation, the native regenerative capabilities of muscle become overwhelmed. [3,4] Instead, skeletal muscle heals with an overactive fibrotic response to volumetric muscle loss (VML) that results in disabling scar tissue. [5] Such injuries are frequent and impose an economic impact on the order of billions of dollars annually.…”

COX‐2 inhibition does not alter wound healing outcomes of a volumetric muscle loss injury treated with a biologic scaffold

“…The majority of the literature on the effects of COX inhibition on skeletal muscle regeneration has been conducted in recoverable injury models (Almekinders & Gilbert, 1986; Bondesen, Mills, Kegley, & Pavlath, 2004; Bondesen, Mills, & Pavlath, 2006; Mishra, Friden, Schmitz, & Lieber, 1995; Obremsky, Seaber, Ribbeck, Garrett, & JR., 1994; Thorsson, Rantanen, Hurme, & Kalimo, 1998) that can be characterized by a well‐orchestrated interplay between the immune and myogenic progenitor cells, which infiltrate the zone of injury. This is definitively not the case for VML as numerous reports have shown (Aguilar et al, 2018, Corona et al, 2017a; Greising et al, 2017b; Nuutila et al, 2017). As such, one might postulate that any positive effects of COX inhibition on inflammation and skeletal muscle regeneration are simply overwhelmed by the magnitude of the immune‐inflammatory response to the VML injury.…”