Early Rehabilitation to Augment Skeletal Muscle Function Following Volumetric Muscle Loss Injury
Authors: Qualls Anita , Nichenko Anna , Southern W. Michael , Agan Zach , Warren Gorden , Greising Sarah , Call Jarrod 
Published: November 2023

Large scale traumatic orthopedic injuries or necessary surgical removal of skeletal muscle represent volumetric muscle loss (VML) injuries, and these injuries result in extensive long‐term dysfunction. Injuries such as VML pose specific limitations to recovery of function because extensive de novo muscle fiber regeneration is inadequate following VML and long‐term functional limitations present as vast reductions in muscle strength and joint range of motion. Current clinical rehabilitation approaches following VML injury are limited, as there is no standard guideline for surgical care or rehabilitation guidelines (acutely or chronically). A major limiting factor to rehabilitation is the amount of remaining muscle tissue following injury, and the adaptability of the remaining tissue is currently not understood. The objective of this study was to investigate the extent to which the remaining muscle tissue after VML injury adapts to early rehabilitation electrical stimulation. Adult male mice underwent an ~20% multi‐muscle VML injury to the posterior compartment (plantarflexor muscles: gastrocnemius, soleus, and plantaris) and were randomized to rehabilitation twice per week beginning 72 hours post‐injury. Mice were divided into two rehabilitation groups: passive ankle range of motion (ROM) serving as a clinical control model, and range of motion with intermittent electrical stimulation (ROM‐E). Passive torque about the ankle joint, a measure of passive muscle stiffness, and sub‐maximal isometric torque about the ankle joint of the plantarflexor muscles was recorded during each therapy session. Cohorts of mice completed 1, 2, or 4 months of therapy prior to a final in vivo assessment of peak isometric torque and contractile fatigue resistance of the plantarflexor muscles. The remaining tissue after VML responded well to therapy as passive stiffness decreased 25% during each therapy session for both ROM and ROM‐E mice (P<0.01) and sub‐maximal torques generated at 20 Hz stimulation improved ~20% week‐to‐week in ROM‐E mice (P<0.04). Peak isometric torque was 18%, 22%, and 14% greater in ROM‐E mice compared to ROM mice at 1, 2, and 4 months, respectively (P≤0.04). Contractile fatigue resistance was 37% greater in ROM‐E mice compared to ROM mice at 4 months (P<0.01). During tissue harvest, the lack of de novo regeneration was confirmed by large mass deficits in the injured limb compared to the contralateral uninjured limb (25% deficit, P<0.01) for both ROM and ROM‐E mice, although there was a trend for greater injured limb muscle mass in ROM‐E mice (P=0.08). In conclusion, the remaining tissue after VML injury is adaptable and early rehabilitation techniques combining range of motion with electrical stimulation may improve the function of the remaining tissue after VML injury. Future testing is needed to assess the metabolic component of rehabilitation intervention as well as the potential negative consequences of musculoskeletal co‐morbidities, such as physical inactivity, associated with VML injury.Support or Funding InformationThis project is funded by the Alliance for Regenerative Rehabilitation Research and Training Grant made possible by: Eunice Kennedy Shriver National Institute Of Child Health & Human Development (NICHD), National Institute Of Neurological Disorders And Stroke (NINDS), and National Institute Of Biomedical Imaging And Bioengineering (NIBIB).