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. At the root of muscle repair is a population of adult muscle stem cells (MuSCs). 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. Unfortunately, these strategies improve structure and function poorly, and the injured tissue shows continued degeneration. In regenerative medicine, novel proposed strategies to treat VML are based on biological scaffolds composed of extracellular matrix proteins. The results of these interventions suggest the need for structural and biochemical frameworks in VML repair. However, the use of biological scaffolds alone may not be sufficient in repairing VML lesions. Recent reports indicate that combining these biological scaffolds with myogenic cells before transplantation results in improved functional and structural repair of VML lesions. In particular, when MuSCs are seeded in biological scaffolds and combined with other cells that share the same muscle microenvironment, or niche, the capacity to repair VML injuries is greatly improved. Importantly, VML is not just about myofibers. In VML injuries, components of the nervous system are also affected. Concomitantly with myofibers, peripheral and intramuscular nerves are ablated and lost from the site of injury. In current state-of-the-art treatments, the exact role of peripheral and intramuscular nerve damage, together with the loss of motor-neuron–musclefiber signaling of trophic factors, are underestimated in VML patients. Understanding the role of denervation resulting from VML injuries in the clinical setting may be pivotal in the design of successful therapies for VML. The study by Corona and colleagues in this issue of the Journal provides an accurate characterization of neural dysfunction after VML injuries. The authors employed a rat tibialis anterior muscle with a VML injury model to examine motor-neuron axotomy in correlation with the temporal neuromuscular and morphologic alterations due to the injury. These are crucial aspects for the understanding of pathogenesis. The clinical condition of VML is indeed characterized by a wide variety of injuries that are heterogeneous in location and size. To advance the development of successful therapeutic design, it is necessary include innervation in the equation. Indeed, recent reports showed that employing tissue-engineering strategies aimed at growing de-novo muscle tissue in VML injuries failed to restore in-vivo forces (recorded through neural stimulation), despite the recovery of ex-vivo forces through direct electrical stimulation. Physical rehabilitation is known to improve muscle function after VML injuries. Consistently, physical exercise has been shown to promote reinnervation of de-novo myofibers within VML lesions, restoring in-vivo forces and suggesting higher degrees of neural plasticity in VML injuries. Corona et al. showed how nerve damage resulting from VML injuries plays a crucial role in VML pathophysiology. Chronic axotomy has previously been proposed as a driver in loss of function after peripheral nerve injury. Interestingly, despite Conflicts of Interest: The author has no conflicts of interest to disclose.