Quantification of Exercise-Induced Sarcomeric Damage in R349P Desmin Knock-In Mice: A New Approach in Myofibrillar Myopathy Research

Holtzhausen C, Schultheis D, Berwanger C, Schuld J, Schlötzer-Schrehardt U, Riehl-Nestler M, Batonnet-Pichon S, Lilienbaum A, Mahabir E, van der Ven P, Fürst D, Schröder R, Clemen C (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Neuropathology and Applied Neurobiology Wiley-Blackwell

Book Volume: 51

Article Number: e70038

Journal Issue: 5

DOI: 10.1111/nan.70038

Abstract

Aims: The classical morphological hallmarks of the clinically and genetically diverse group of human myofibrillar myopathies are signs of myofibrillar degeneration and desmin-positive protein aggregates. The local sarcomeric enrichment of filamin-C and xin actin-binding repeat-containing proteins 1 and 2 (xirp 1 and xirp 2) is a marker of myofibrillar damage. This work aimed to (i) address filamin-C- and xirp 1/2-positive sarcomeric lesions in desminopathy mouse models, (ii) develop an approach to quantifying xirp 1/2-positive sarcomeric lesions, and (iii) study the effects of acute physical exercise on sarcomeric lesion formation in R349P desmin knock-in mice, which are a model of human R350P desminopathy. Methods: Sarcomeric lesions were visualised by xirp 1/2 and filamin-C immunofluorescence in soleus muscles from R349P and R405W desmin knock-in, desmin knock-out and W2711X filamin-C knock-in mice. The open-source software QuPath was used to analyse xirp 1/2 confocal immunofluorescence images of soleus muscle from nonexercised and treadmill-exercised R349P desmin knock-in mice. Results: Filamin-C and xirp 1/2 stained muscles revealed the presence of congenerous sarcomeric lesions in heterozygous and homozygous R349P and R405W desmin knock-in, homozygous desmin knock-out and heterozygous and homozygous W2711X filamin-C knock-in mice. Quantitative analysis of R349P desmin knock-in mice showed (i) significantly more lesions in nonexercised heterozygous mice, with an even more pronounced increase in homozygous animals, as compared to wild-type, and (ii) a significant increase in sarcomeric lesions per mm2 in heterozygous mice and wild-type siblings subjected to strenuous treadmilling. Conclusions: A QuPath workflow to quantify sarcomeric lesions using xirp 1/2 immunofluorescence images showed augmented densities of lesions in R349P desminopathy mice and after treadmill exercise. Eccentric and high-intensity physical activity may exhibit a disease-promoting effect on skeletal muscles in desminopathy.

Authors with CRIS profile

Christian Holtzhausen Department of Medicine 5 – Haematology and Oncology Ursula Schlötzer-Schrehardt Department of Ophthalmology Rolf Schröder Professur für Neuropathologie

Involved external institutions

Deutsches Zentrum für Luft- und Raumfahrt e.V. (DLR) / German Aerospace Center DE Germany (DE) Rheinische Friedrich-Wilhelms-Universität Bonn DE Germany (DE) Universitätsklinikum Köln DE Germany (DE) Université Sorbonne Paris Cité FR France (FR)

How to cite

APA:

Holtzhausen, C., Schultheis, D., Berwanger, C., Schuld, J., Schlötzer-Schrehardt, U., Riehl-Nestler, M.,... Clemen, C. (2025). Quantification of Exercise-Induced Sarcomeric Damage in R349P Desmin Knock-In Mice: A New Approach in Myofibrillar Myopathy Research. Neuropathology and Applied Neurobiology, 51(5). https://doi.org/10.1111/nan.70038

MLA:

Holtzhausen, Christian, et al. "Quantification of Exercise-Induced Sarcomeric Damage in R349P Desmin Knock-In Mice: A New Approach in Myofibrillar Myopathy Research." Neuropathology and Applied Neurobiology 51.5 (2025).

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