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. The gene discussed is DES; the disease is Desminopathy.