(B-71) Dysregulation of the Normal Wound Healing Cascade in Volumetric Muscle Loss Injury

Introduction:: Volumetric muscle loss (VML) includes both traumatic lesions and surgical removals of a large muscle area and the consequent impairment of regenerative capabilities. VML is a devastating, pathological condition that may occur due to trauma such as crush injuries, blasts, or trauma-like compartment syndromes and open bone fractures. While it is known that the normal wound healing process is somehow disrupted in VML injuries, so far little has been done to examine the underlying signaling mechanisms that cause this type of injury to develop differently. The goal of this study is to investigate the abnormalities in signaling pathways that occur in VML injuries to potentially uncover therapeutic targets.


Materials and Methods:: Adult male and female C57BL/6J mice had the left tibialis anterior muscle (TA) exposed and a full thickness VML defect (3 mm diameter for male mice, 2 mm for female mice) was created using a sterile biopsy punch. The contralateral limb was left uninjured to serve as an internal comparative control. Animals were then assigned to four different recovery time points (4, 7, 11, and 15 days). At each time point, the TAs were harvested for transcriptomics, proteomics, and histology. Animals in the 15 day group also underwent TA muscle electrophysiology.


Results, Conclusions, and Discussions:: In the mice models, the tissue repair was limited as evidenced by both the gross appearance (atrophied) and decreased contractile force output (Figure 1A and 1B). The LTAs were noticeably atrophied at every time point and the force output was dramatically decreased (approximately 20-45% of normal) 15 days after injury. Transcriptomic analysis revealed significant differences in factors regulating inflammation, myogenesis (Figure 1C) and angiogenesis (Figure 1D) in response to VML injury to the TA muscle from what would be expected in the healing of a more normal injury. Many of the physical effects measured in the VML models (poor force and mass recovery) are consistent with the changes detected in the transcriptome data, such as the low expression of myogenic and angiogenic genes. Of particular note, many genes related to immune cell dynamics, including t-cell dynamics, were disrupted.


This study revealed that gene expression in VML muscle injury differed in a variety of ways from what has been reported for models of milder muscle injuries that achieve full recovery. Pro-regenerative genes like MYOD1 and VEGFA, which play a significant role in normal skeletal muscle regeneration, had notably low expression in VML injured muscle, while many inflammatory genes that have been linked to poor healing in chronic wounds remained highly expressed at all time points of the study. To improve regeneration in VML injury, it would be of significant value to find ways to push gene expression towards that which would be seen in normal, complete muscle regeneration. One such may be to modulate the immune response by injecting T-regulatory cells, which play an important role in tamping down inflammation and transitioning the wound environment to a more pro-regenerative state.




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