Acute mitochondrial reactive oxygen species emissions drive mitochondrial dysfunction after traumatic muscle injury in male mice.

Volumetric muscle loss (VML) is characterized by contractile weakness, dysfunctional mitochondrial bioenergetics, and poor rehabilitation plasticity. A hyperpolarized mitochondrial membrane potential is one attribute of the dysfunction bioenergetics and can lead to excessive reactive oxygen species (ROS) emissions. The primary objective of this study was to define the role of acute ROS emissions after VML injury. Male C57BL/6J mice were randomized into experimental and control groups. A time course of ROS emissions and antioxidant buffering capacity (AoxBC) for VML-injured muscles was established across the first 60-days post-injury (dpi). SS-31, a mitochondrial-targeted peptide, was administered s.c. (8mg/kg/d) for up-to 14-dpi and specific electron transport chain complex ROS emissions and mitochondrial bioenergetics were investigated. SS-31 and wheel running were combined in a regenerative rehabilitation model to determine if attenuating acute ROS emissions improved adaptive capability of the remaining muscle. Lipidomic and proteomic analyses were conducted to explore mechanisms of SS-31 benefit after VML. ROS emissions were greater and AoxBC less during the first 14-dpi and this was associated with dysfunctional mitochondrial bioenergetics regardless of carbohydrate or fat fuel substrate. Complexes I, II, and III were identified as the primary sources of ROS emissions. SS-31 attenuated ROS emissions at both 7- and 14-dpi and led to greater mitochondrial respiratory conductance and efficiency out to 30-dpi. Regenerative rehabilitation did not produce greater contractile adaptations, but there was modest evidence of greater metabolic adaptations compared to rehabilitation alone. Lipidomic and proteomic analyses suggest that SS-31 contributes to redox protein abundance alterations after VML injury.