Early rehabilitation for volumetric muscle loss injury augments endogenous regenerative aspects of muscle strength and oxidative capacity

Abstract

BackgroundVolumetric muscle loss (VML) injuries occur due to orthopaedic trauma or the surgical removal of skeletal muscle and result in debilitating long-term functional deficits. Current treatment strategies do not promote significant restoration of function; additionally appropriate evidenced-based practice physical therapy paradigms have yet to be established. The objective of this study was to develop and evaluate early rehabilitation paradigms of passive range of motion and electrical stimulation in isolation or combination to understand the genetic and functional response in the tissue remaining after a multi-muscle VML injury.MethodsAdult male mice underwent an ~ 20% multi-muscle VML injury to the posterior compartment (gastrocnemius, soleus, and plantaris muscle) unilaterally and were randomized to rehabilitation paradigm twice per week beginning 2 days post-injury or no treatment.ResultsThe most salient findings of this work are: 1) that the remaining muscle tissue after VML injury was adaptable in terms of improved muscle strength and mitigation of stiffness; but 2) not adaptable to improvements in metabolic capacity. Furthermore, biochemical (i.e., collagen content) and gene (i.e., gene arrays) assays suggest that functional adaptations may reflect changes in the biomechanical properties of the remaining tissue due to the cellular deposition of non-contractile tissue in the void left by the VML injury and/or differentiation of gene expression with early rehabilitation.ConclusionsCollectively this work provides evidence of genetic and functional plasticity in the remaining skeletal muscle with early rehabilitation approaches, which may facilitate future evidenced-based practice of early rehabilitation at the clinical level.Electronic supplementary materialThe online version of this article (10.1186/s12891-018-2095-6) contains supplementary material, which is available to authorized users.

PGC-1α overexpression partially rescues impaired oxidative and contractile pathophysiology following volumetric muscle loss injury

“…With the goal of developing treatment strategies capable of improving the long-term functional deficits in VML injured muscle tissue, we sought to elucidate the early effects of VML on contractility and oxidative capacity of the remaining skeletal muscle. In order to best characterize the impact of VML on skeletal muscle, we used a model of VML injury that has been shown to reproducibly recapitulate the injury on primary hind limb locomotor muscles (i.e., the plantar flexor muscles [gastrocnemius, soleus, plantaris]) and results in a chronic functional deficit (15). In agreement with prior reports,(24-26) muscle contractile function was reduced by ~80% when compared to uninjured muscles for injury naïve mice at both 3 and 7 days post-injury, even after normalizing to the injured muscle mass (P<0.001; Fig.…”

“…chronic-intermittent electrical nerve stimulation and/or passive range of motion exercises (15) and collectively found modest contractile adaptations are possible. However, clinical reports have indicated that patients only see moderate improvements and then hit the ceiling where further physical therapy, no matter the type or intensity, does not result in an increase in function (16)(17)(18).…”

“…Noteably, Aurora and colleagues reported a reduced metabolic gene response (i.e., PGC-1 and SIRT-1) in VML-injured muscle following voluntary wheel running compared to uninjured muscle (11). Furthermore, Greising and colleagues showed that mitochondrial respiration rates measured from both the VML-injured and contralateral uninjured mouse muscles were less than that of injury naïve mice suggesting a more chronic and systemic effect of VML injury on muscle oxidative capacity (15). Therefore, VMLinjured patients may be susceptible to lifelong impairments in skeletal muscle oxidative capacity that can result in additional comorbidities as systemic reductions in skeletal muscle oxidative capacity are associated with an increased risk for a host of disorders such as diabetes (19) and cardiovascular disease (20).…”

Pre-Innervated Tissue Engineered Muscle Promotes a Pro-Regenerative Microenvironment Following Volumetric Muscle Loss

“…Early physical rehabilitation involving exercise has been shown to benefit patients with VML in recovering muscle force and range of motions 58 . Similarly, rehabilitative exercise in conjunction with bioengineered constructs augments functional restoration in murine models of VML by promoting formation of AchR clusters and mature NMJs [59][60][61][62] . One of the key findings of the present study is that pre-innervated constructs augments AchR clustering and NMJ formation.…”

Musculoskeletal Regeneration, Rehabilitation, and Plasticity Following Traumatic Injury

“…It is currently unknown at this time what specific effect protracted in-flammation has on satellite cell viability and function within the remaining portion of the muscle; however, given the necessity of local satellite cells for muscle regeneration and their importance to plasticity, research investigating the quality of chronically injured muscle after VML, is highly needed. Other salient observations following VML injury include motor neuron axotomy, loss of neuromuscular junctions, heightened oxidative stress, devascularization, and mitochondrial dysfunction [83][84][85]; all of these may be deleterious to regenerative healing and the capacity to respond to tissue level physical therapies.…”