Dystrophin is a mechanical tension modulator


Hofemeier AD, Muenker TM, Herkenrath F, Ristau M, Brandt M, Shahriyari M, Tiburcy M, Zimmermann WH, Lenz C, Mamchaoui K, Bigot A, Gilbert PM, Betz T




bioRxiv 2022.12.23.521750.


Duchenne muscular dystrophy (DMD) represents the most common inherited muscular disease, where increasing muscle weakness leads to loss of ambulation and premature death. DMD is caused by mutations in the dystrophin gene, and is known to reduce the contractile capacity of muscle tissue both in vivo, and also in reconstituted systems in vitro. However, these observations result from mechanical studies that focused on stimulated contractions of skeletal muscle tissues. Seemingly paradoxical, upon evaluating bioengineered skeletal muscles produced from DMD patient derived myoblasts we observe an increase in unstimulated contractile capacity that strongly correlates with decreased stimulated tissue strength, suggesting the involvement of dystrophin in regulating the baseline homeostatic tension level of tissues. This was further confirmed by comparing a DMD patient iPSC line directly to the gene-corrected isogenic control cell line. From this we speculate that the protecting function of dystrophin also supports cellular fitness via active participation in the mechanosensation to achieve and sustain an ideal level of tissue tension. Hence, this study provides fundamental novel insights into skeletal muscle biomechanics and into a new key mechanical aspect of DMD pathogenesis and potential targets for DMD drug development: increased homeostatic tissue tension.