# Role of titin in the pathophysiology of diaphragm weakness during mechanical ventilation

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2022 · $506,920

## Abstract

7. SUMMARY.
The long-term goal of this proposal is to gain detailed understanding of how the diaphragm – the main muscle
of respiration – rapidly weakens in response to mechanical unloading, and of the mechanisms whereby the
giant elastic protein titin influences this response.
The diaphragm is a unique muscle in that it is constantly subjected to mechanical loading. Recent work
suggests that diaphragm strength is remarkably sensitive to mechanical unloading, as occurs during
mechanical ventilation in the ICU. How unloading affects diaphragm strength is poorly understood. Increasing
this understanding is critically important: within hours, diaphragm unloading during mechanical ventilation
causes diaphragm weakness in critically ill patients, contributing to weaning failure. The search for the
molecular triggers for the development of diaphragm weakness is ongoing. The potential role of
mechanosensor proteins, that link unloading to protein turnover, is under-explored but an exciting concept
that needs to be studied. A candidate mechanosensor is titin, a giant elastic protein that has been suggested
to sense mechanical stress and link this to trophic signalling pathways. This proposal’s aims to understand
mechanosensing in the diaphragm in health and disease, and the role of titin therein.
Aim 1 will critically test how titin affects muscle trophicity. We will use unilateral diaphragm denervation
(UDD). A property that can be observed during UDD is an initial hypertrophy response and we have shown that
this hypertrophy of the denervated hemidiaphragm is caused by cyclic passive stretch of diaphragm fibers, and
that titin’s elastic properties dictate the magnitude of the response. In this Aim we will identify the titin-based
signalling pathways involved. Aim 2 determines the role of titin’s elasticity in PEEP ventilation-induced
longitudinal diaphragm atrophy. This work builds on our recent finding that mechanical ventilation with
PEEP, which unloads the diaphragm at a shortened length, causes longitudinal atrophy of fibers. Pilot data
suggest that titin-based mechanosensing modulates this response. To critically test the role of titin, we will
study the effect of PEEP ventilation on longitudinal atrophy in two titin KO mouse models: one with increased
titin stiffness and one with lowered. In Aim 3 we will use unique diaphragm biopsies of critically ill
patients to validate the findings from aim 1&2 and study whether titin-based mechanosensing contributes to
diaphragm weakness. Up/downregulated titin binding proteins will be determined, the significance of which is
tested in mouse models through genetic deletion.
The innovation of this proposal lies in the novel research foci with innovative guiding hypotheses, its innovative
mouse models, unique diaphragm biopsies from mechanically ventilated critically ill patients, and its novel
experimental tools. The proposal’s integrative approach is expected to lead to a significant step forward in
our under...

## Key facts

- **NIH application ID:** 10438849
- **Project number:** 5R01HL121500-09
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Coen Ottenheijm
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $506,920
- **Award type:** 5
- **Project period:** 2014-01-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10438849

## Citation

> US National Institutes of Health, RePORTER application 10438849, Role of titin in the pathophysiology of diaphragm weakness during mechanical ventilation (5R01HL121500-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10438849. Licensed CC0.

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