Abstract
Volumetric muscle loss (VML) injury is characterized by a non-recoverable loss of muscle fibers due to ablative surgery or severe orthopaedic trauma, that results in chronic functional impairments of the soft tissue. Currently, the effects of VML on the oxidative capacity and adaptability of the remaining injured muscle are unclear. A better understanding of this pathophysiology could significantly shape how VML-injured patients and clinicians approach regenerative medicine and rehabilitation following injury. Herein, the data indicated that VML-injured muscle has diminished mitochondrial content and function (i.e., oxidative capacity), loss of mitochondrial network organization, and attenuated oxidative adaptations to exercise. However, forced PGC-1α over-expression rescued the deficits in oxidative capacity and muscle strength. This implicates physiological activation of PGC1-α as a limiting factor in VML-injured muscle’s adaptive capacity to exercise and provides a mechanistic target for regenerative rehabilitation approaches to address the skeletal muscle dysfunction.
Highlights
Oxidative capacity is a cornerstone of skeletal muscle health, and for the past 40 years, we have known that the most robust physiologic adaptation to regularly scheduled physical activity is an increase in oxidative capacity[1,2]
In order to best characterize the impact of volumetric muscle loss (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 and results in a chronic functional deficit, which have been evaluate up to four months post-injury[15]
To determine if VML affects muscle oxidative capacity early after injury, mitochondrial function was assessed at 3 and 7 days post-VML via high-resolution respirometry of permeabilized fibers isolated from portions of the remaining muscle adjacent to the injury site
Summary
Oxidative capacity is a cornerstone of skeletal muscle health, and for the past 40 years, we have known that the most robust physiologic adaptation to regularly scheduled physical activity (i.e., exercise/overload training) is an increase in oxidative capacity[1,2]. Improvements in muscle oxidative capacity are made possible with exercise training through adaptations affecting the density and function of the intramuscular mitochondrial network. The transcription factor PGC-1α (peroxisome proliferator-activated receptor gamma, coactivator 1 alpha) is considered a critical molecular modulator of skeletal muscle oxidative plasticity because it regulates gene expression patterns for expansion of the mitochondrial network (i.e., mitochondrial biogenesis), angiogenesis, and motor neuron associated adaptations with exercise training[4,5,6]. Investigations of physical rehabilitation following VML have resulted in, at best, modest improvements in muscle function following VML injury without any physiological rationale or mechanistic understanding for the lack of significant response. An important innovation of the current work was the use of 2-photon microscopy to investigate changes in the structural integrity of the mitochondrial network as this aspect of mitochondrial physiology is likely disrupted following VML injury. The combination of all of these proven techniques has allowed for extensive characterization of multiple aspects of mitochondrial physiology in VML-injured muscle, which provides a new and unique prospective of the impacts of VML on mitochondria
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