Capn1-KO Mouse

Capn1, also known as calpain1, is an intracellular Ca2+-regulated cysteine protease. It plays a role in various biological processes such as autophagy-lysosomal pathway regulation, and is involved in multiple cellular functions [2]. Dysregulation of Capn1 can impact key cellular events, making it biologically significant in understanding normal cell function and disease mechanisms. Genetic models, like gene knockout (KO) mouse models, can be valuable in studying Capn1's function.

In arrhythmogenic cardiomyopathy (ACM), homozygous Dsg2 mutant mice (a model of ACM) show Ca2+ overload, which activates CAPN1. CAPN1 then associates with mitochondria and cleaves apoptosis-inducing factor (AIF), leading to myocyte cell death. Overexpressing calpastatin (CAST), an endogenous CAPN1 inhibitor, in myocytes protects against Ca2+ overload-induced necrosis [1]. In cerebral ischemia, genetic and pharmacological inhibition of CAPN1 in rat permanent middle cerebral occlusion in vivo model and oxygen-glucose–deprived primary neuron in vitro model attenuates ischemia-induced lysosomal membrane permeabilization and autophagic substrate accumulation, highlighting its role in cerebral ischemia-induced neuronal damage [2].

In conclusion, Capn1 is a crucial protease involved in regulating autophagy-lysosomal pathway and Ca2+-related cellular events. Studies using KO mouse models have revealed its significance in diseases like arrhythmogenic cardiomyopathy and cerebral ischemia, providing insights into potential therapeutic targets for these conditions.

References:

1. Chelko, Stephen P, Keceli, Gizem, Carpi, Andrea, Di Lisa, Fabio, Paolocci, Nazareno. . Exercise triggers CAPN1-mediated AIF truncation, inducing myocyte cell death in arrhythmogenic cardiomyopathy. In Science translational medicine, 13, . doi:10.1126/scitranslmed.abf0891. https://pubmed.ncbi.nlm.nih.gov/33597260/

2. Liu, Yueyang, Che, Xiaohang, Zhang, Haotian, Yang, Jingyu, Zhou, Ming-Sheng. 2021. CAPN1 (Calpain1)-Mediated Impairment of Autophagic Flux Contributes to Cerebral Ischemia-Induced Neuronal Damage. In Stroke, 52, 1809-1821. doi:10.1161/STROKEAHA.120.032749. https://pubmed.ncbi.nlm.nih.gov/33874744/