Characterization of a Kbtbd13 ‐Deficient Mouse Model That Recapitulates Nemaline Myopathy With Mutations in The KBTBD13 Gene

Background Nemaline myopathy (NM) is the most common non‐dystrophic congenital myopathy and is characterized by muscle weakness. Recently a novel implicated gene was discovered ‐ KBTBD13 – of which the function of its protein product is unknown. NM patients with KBTBD13 mutations have muscle weakness and show a typical slowness of movement. Here, we generated a mouse model that lacks the kbtbd13 gene to obtain insight into the role of this new gene and its protein product and to elucidate the pathophysiology of this new form of NM. Methods Kbtbd13 ‐KO mice are viable and live into adulthood. Muscle weights of cardiac and skeletal muscle were collected. Intact soleus muscles of 3 month‐old male kbtbd13 ‐KO and wild‐type (WT) mice were used for in vitro experiments. Muscle tendons were attached to a force transducer and a length motor. Muscles were electrically activated by field stimulation at 30°C. Results Maximal tetanic force at 150Hz was reduced in kbtbd13 ‐KO (n=10). The relative force‐frequency relationship in kbtbd13 ‐KO mice was shifted to the left compared to WT mice. Both activation and relaxation kinetics were slower in kbtbd13 ‐KO mice. Muscle weight data reveal atrophy of skeletal muscles, whereas the cardiac muscle shows hypertrophy of the left ventricle. Conclusion Kbtbd13 ‐KO mice phenocopy the normal life span and typical muscle weakness observed in NM patients with mutations in KBTBD13 . Hence, we present a novel NM mouse model that is a useful tool to elucidate the role of this new gene and its protein product and to study the mechanism underlying muscle weakness observed in patients.