PROJECT SUMMARY
Current soft tissue repair techniques have not been able to reverse the pathological changes that occur following
volumetric muscle loss (VML) injury. The key event in the etiology of VML injury is the bulk loss of regenerative
cues provided by the underlying extracellular matrix (ECM). Persistent inflammation is a hallmark of VML injury,
and it is well-established chronic inflammation impairs skeletal muscle regeneration. To reverse the pathology
of VML injury, our group and others are exploring the use of bioengineered scaffolds such as decellularized
muscle tissue (i.e., regenerative medicine strategies) as a means of restoring lost cellular and architectural cues
to trigger muscle recovery. However, the results across several groups appear to suggest that a regenerative
ceiling exists; typically restoring no more than 80% of the contractile force lost to VML injury. What has been
overlooked is the importance of rebuilding the force environment using rehabilitative medicine (i.e., exercise).
However, combined rehabilitative and regenerative strategies have only improved force recovery up to the
current regenerative ceiling. The premise of the proposed research is twofold. This project seeks to determine
the appropriate exercise prescription (intensity and duration) that will provide an optimal force recovery response.
In addition, this project postulates that delivery of a concurrent (hypertrophic and endurance) stimulus (via
rehabilitation) into the VML repair site will enhance the performance of regenerative medicine. The premise is
supported by a preponderance of evidence, including our own preliminary data, which suggests that endurance
and hypertrophic-inducing exercise can be used to decrease inflammation, increase cellular metabolism, and
enhance muscle fiber growth, each of which have known benefits for skeletal muscle regeneration. We will
examine the impact of endurance exercise and endurance exercise with an added resistance component on
VML recovery during Aim 1 and 2 experiments, respectively. Additionally, we will use pharmacological methods
(i.e., resolvin D1) to alter the initial inflammatory period to attenuate chronic inflammation.
We propose the following specific aims:
Aim 1: Determine the efficacy of treadmill-based endurance exercise on attenuating the inflammatory
response during muscle recovery following regenerative repair of VML injury.
Aim 2: Determine whether addition of a hypertrophic stimulus via PoWeR will enable improved
regeneration capabilities beyond current regenerative ceiling.
This study has the potential to deliver innovative new knowledge that will advance the search for an effective
VML treatment strategy.
