# Targeting mitochondrial permeability transition to attenuate adverse muscle impact in sepsis

> **NIH NIH R21** · UNIVERSITY OF FLORIDA · 2024 · $193,188

## Abstract

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.

## Key facts

- **NIH application ID:** 10950721
- **Project number:** 1R21AR084591-01
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Russell T Hepple
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $193,188
- **Award type:** 1
- **Project period:** 2024-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10950721

## Citation

> US National Institutes of Health, RePORTER application 10950721, Targeting mitochondrial permeability transition to attenuate adverse muscle impact in sepsis (1R21AR084591-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10950721. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*