Establishing well-described mouse models of hereditary diseases is increasingly important for testing new therapeutic approaches, such as gene replacement therapy. In particular, a detailed description of muscle pathology, especially at early timepoints of the disease, is crucial for determining the optimal timepoint for drug delivery and evaluation of therapeutic success. In this study, we aimed to characterize and quantify the muscle pathology and myofibre morphology of different muscles in a new mouse model for calpainopathy as an example of the heterogenous group of limb girdle muscular dystrophies compared to wildtype controls during the disease. We analysed motor function and muscle tissue of wildtype and Capn3-transgenic mice per gender from 1.5 to 15 months of age. While transgenic mice did not develop restrictions in motor function, tested with grip strength measurement, beam walk and four limb wire hanging test, during this period, gastrocnemius, soleus and psoas muscles showed progressive histopathological and ultrastructural changes. Importantly, we also detected gender-specific differences in general muscle structure and in muscle pathology in the mouse model of calpainopathy. We developed a score to classify pathology of muscles in this mouse model using percentage of myocytes with centralized nuclei to increase objectivity and comparability when using this mouse model.