Regenerative Repair of Volumetric Muscle Loss Injury is Sensitive to Age

Abstract

In this study, the influence of age on effectiveness of regenerative repair for the treatment of volumetric muscle loss (VML) injury was explored. Tibialis anterior (TA) VML injuries were repaired in both 3-and 18-monthold animal models (Fischer 344 rat) using allogeneic decellularized skeletal muscle (DSM) scaffolds supplemented with autologous minced muscle (MM) paste. Within the 3-month animal group, TA peak contractile force was significantly improved (79% of normal) in response to DSM+MM repair. However, within the 18month animal group, muscle force following repair (57% of normal) was not significantly different from unrepaired VML controls (59% of normal). Within the 3-month animal group, repair with DSM+MM generally reduced scarring at the site of VML repair, whereas scarring and a loss of contractile tissue was notable at the site of repair within the 18-month group. Within 3-month animals, expression of myogenic genes (MyoD, MyoG), extracellular matrix genes (Col I, Col III, TGF-b), and key wound healing genes (TNF-a and IL-1b) were increased. Alternatively, expression was unchanged across all genes examined within the 18-month animal group. The findings suggest that a decline in regenerative capacity and increased fibrosis with age may present an obstacle to regenerative medicine strategies targeting VML injury.

New Surgical Model for Bone–Muscle Injury Reveals Age and Gender-Related Healing Patterns in the 5 Lipoxygenase (5LO) Knockout Mouse

“…To investigate the role of 5LO in the process of simultaneous bone and muscle healing, we developed a new surgical model of MSK injury in 5LOKO animals. Despite the importance of in vivo investigation for the comprehension of bone healing, previous rodent models of bone and muscle damage focus their attention exclusively on bone formation (14,74), while the majority of studies of the on MSK healing addresses skeletal muscle (23,75) or bone, but separately (24,39). In our study, we performed a moderated simultaneous bone and muscle surgical damage, with a 1-mm diameter defect in muscle and a 0.5-mm diameter defect in the subjacent bone (Figure 2A), in order to avoid further surgical complications, such as femur fracture in aged animals.…”

“…Apart from the specificity of each cell type involved in skeletal muscle and/or bone regeneration, general tissue healing postinjury requires an initial and transient inflammatory phase, with release of several cytokines and inflammatory mediators, such as AA-derived signaling lipid mediators released from ciclooxigenase-2 (COX2) and 5-Lipoxygenase (5LO) pathways (22)(23)(24). These processes inherent to the inflammatory response are essential in directing vascular events and leukocytes migration, through the release of PGs and LTs (LTB4 and/or CysLTs), respectively (25,26).…”

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

“…Repair of skeletal muscle involves the complex but coordinated processes of satellite cell activation and proliferation, myoblast proliferation and differentiation, inflammation,and extracellular matrix remodelling (Tidball, 2011). However, following large traumatic loss of muscle tissue, or volumetric muscle loss (VML), the endogenous repair mechanisms of skeletal muscle are overwhelmed, often leading to overt fibrosis and chronic inflammation at the site of injury (Kim et al., 2020). VML results in permanent functional deficits as well as cosmetic deficits (Grogan & Hsu, 2011; Terada et al., 2001).…”

“…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). Persistent inflammation inhibits myogenesis and enhances the fibrotic response, which inhibits recovery of skeletal muscle (Perandini et al, 2018).…”

“…There is currently no standard of care for VML that restores function to the injured skeletal muscle. Recently, research groups developing regenerative therapies have investigated the use of biological scaffolds, decellularized tissue and autologous tissue implantation in order to promote satellite cell migration into the defect site (Corona et al, 2013a;Das et al, 2020;Garg et al, 2014;Kim et al, 2020). Despite these efforts, it appears implantation alone is insufficient to elicit a robust regenerative response possibly due to lack of a proper stimulus to promote cell migration and growth factor release.…”