Pathophysiology of Volumetric Muscle Loss Injury

Abstract

Volumetric muscle loss (VML) injuries are prevalent in civilian and military trauma patients and are known to impart chronic functional deficits. The frank loss of muscle tissue that defines VML injuries is beyond the robust reparative and regenerative capacities of mammalian skeletal muscle. Given the nature of VML injuries, there is a clear need to develop therapies that promote de novo regeneration of skeletal muscle fibers, which can integrate with the remaining musculature and restore muscle strength. However, the pathophysiology of VML injuries is not completely defined, and, therefore, there may be other opportunities to improve functional outcomes other than de novo regeneration. Herein, clinical and preclinical studies of VML were reviewed to ascertain salient manifestations of VML injury that can impair limb function and muscle strength. The limited clinical data available highlighted proliferative fibrosis secondary to VML injury as a viable target to improve limb range of motion. Selected preclinical studies that used standardized neuromuscular functional assessments broadly identified that the muscle mass remaining after VML injury is performing suboptimally, and, therefore, percent VML strength deficits are significantly worse than can be explained by the initial frank loss of contractile machinery. Potential mechanisms of suboptimal strength of the remaining muscle mass suggested within the literature include intramuscular nerve damage, muscle architectural perturbations, and diminished transmission of force. Collectively, both clinical and preclinical data indicate a complex pathophysiology after VML that presents multiple therapeutic targets. This is a work of the US Government and is not subject to copyright protection in the USA. Foreign copyrights may apply. Published by S. Karger AG, Basel

Impact of volumetric muscle loss injury on persistent motoneuron axotomy

“…Various preclinical studies have investigated the magnitude of skeletal muscle dysfunction in a range of VML models at chronic time points (i.e., greater than 1 month) . Functional strength deficits observed are disproportionately larger in comparison to the injury‐related loss of muscle mass .…”

“…Various preclinical studies have investigated the magnitude of skeletal muscle dysfunction in a range of VML models at chronic time points (i.e., greater than 1 month) . Functional strength deficits observed are disproportionately larger in comparison to the injury‐related loss of muscle mass . Possible physiological mechanisms for the functional limitations following injury relate to aberrant muscle fiber regeneration, excitation‐contraction coupling failure, muscle fiber architectural misalignment and dampened force transmission.…”

Robust inflammatory and fibrotic signaling following volumetric muscle loss: a barrier to muscle regeneration

“…However, after surgical or traumatic loss of a critical mass of muscle, also known as volumetric muscle loss 1 (VML), this endogenous regenerative competence is overwhelmed. Rather VML has been shown to induce robust scar deposition, fibrotic supplantation, loss of function, and serious morbidity 2 . These outcomes have been postulated to result from the ablation of resident regenerative progenitors in addition to connective tissue and basement membrane, which provide structural, biochemical, and mechanical cues to guide regeneration 3 .…”

Volumetric muscle loss: Including nerves into the equation

“…The interdependent relationship between skeletal muscle and nerves is well characterized and has been known since the early studies by Galvani in the 18th century . However, the exact role of damaged motor neurons in the context of severe injuries of skeletal muscle tissue is still not fully understood . Overall, skeletal muscle has a remarkable capacity to regenerate from injuries.…”

“…These MuSCs reside normally under the basal lamina of muscle fibers in a quiescent state, where they can activate and proliferate in response to injuries to restore tissue structure and function . However, after a permanent loss of tissue mass caused by a trauma or surgical removal, such as in the case of volumetric muscle loss (VML), MuSCs are incapable of regenerating tissue . Current state‐of‐the‐art treatments of VML are limited to muscle flaps or muscle transfer within the area of tissue defects .…”