Files
Abstract
Volumetric muscle loss (VML) is characterized by a large volume of muscle tissue being removed from the body due to surgery or severe trauma. The remaining muscle after VML has poor function and unknown effects on oxidative capacity and adaptive potential during physical rehabilitation. We sought to investigate the oxidative capacity and plasticity of the remaining skeletal muscle after VML injury. We found that VML mitochondrial respiratory function at 3 and 7 days post injury was severely impaired (38% and 53% of control, P<0.001). In an attempt to correct these mitochondrial deficits, we subjected VML injured mice to voluntary wheel running (WR). After 4 weeks of WR, mitochondrial function was ~23% greater in the uninjured limb of VML+WR mice compared to VML without WR, but mitochondrial function in the injured limb of VML+WR mice was not different from VML alone, suggesting VML injury prevents oxidative adaptations to exercise (P<0.001). To determine if a faulty oxidative signaling cascade (i.e., PGC-1a) was responsible for impaired metabolic adaptation in the VML-injured muscle, direct muscle activation via sciatic nerve electrical stimulation was used to initiate oxidative gene transcription in control (CON) and VML mice. The stimulated muscle in CON mice had ~4-fold greater PGC-1a gene expression than the unstimulated muscle; however, there was no effect of stimulation on PGC-1a expression in VML mice (Interaction: P<0.001) suggesting VML injury attenuates oxidative gene regulation. PGC-1a (CMV promoter) transfection was performed to bypass endogenous PGC-1a activation pathways. Forced expression of PGC-1a resulted in ~33% and ~31% greater mitochondrial function in CON+ PGC-1a and VML+ PGC-1a mice, respectively, compared to VML alone (P<0.001), and VML+ PGC-1a mice had 47% greater muscle strength than VML alone (P<0.001). In conclusion, PGC-1a activation is the limiting factor impairing oxidative plasticity in VML-injured muscle; and improving oxidative capacity of the remaining muscle after VML injury improves recovery of strength.