Targeting mitochondrial permeability transition to attenuate adverse muscle impact in sepsis

Not only is skeletal muscle a target in sepsis that contributes to worse patient health outcomes, including problems weaning from mechanical ventilation and a greater risk of death, but through release of mtDNA there is strong potential for skeletal muscle to play an amplifying role in driving the systemic inflammation by activating

damage associated molecular patterns (DAMPs). Therefore, identifying treatments to attenuate adverse muscle impact with sepsis is one key to improving patient outcomes. This high risk-high reward R21 application explores the role of an event known as mitochondrial permeability transition (mPT) in skeletal muscle as a mechanism for

both muscle dysfunction and mtDNA-mediated escalation of systemic inflammation in sepsis. mPT is triggered by Ca2+ to cause formation of a non-specific pore across the mitochondrial inner membrane, where phosphorylation and/or acetylation of the mitochondrial peptidyl-prolyl cis-trans isomerase protein cyclophilin D

(CypD) reduces the amount of Ca2+ needed to trigger mPT, whereas knockout of CypD increases the amount of Ca2+ needed to trigger mPT. Notably, mPT has been demonstrated to occur in various tissues with sepsis but has so far not been considered in skeletal muscle, despite several studies noting an accumulation in skeletal

muscle of mitochondria with morphological features that are established consequences of mPT. In addressing the outcomes of mPT in skeletal muscle, we have shown that mPT causes atrophy and dismantling of the acetylcholine receptor cluster at the neuromuscular junction, and other impacts are likely to be revealed with

further study. Furthermore, mtDNA is released from mitochondria during mPT and higher mtDNA levels in the circulation predict poor outcomes in septic patients. Considering that skeletal muscle constitutes up to 40% of body mass, mPT occurring in skeletal muscle has strong potential to play a major role in driving the increase in

circulating mtDNA in sepsis. In addressing this issue, we will test the central hypothesis that knockout of the mPT-promoting protein CypD in skeletal muscle will attenuate both muscle dysfunction and systemic inflammation in sepsis to yield improved outcomes in septic mice. We expect that our studies will demonstrate

that in the context of experimental sepsis skeletal muscle-specific CypD knockout will confer protection to skeletal muscle, attenuate the increase in circulating mtDNA to limit systemic inflammation, and thereby promote better outcomes in sepsis.