C3KO mouse expression analysis: downregulation of the muscular dystrophy Ky protein and alterations in muscle aging

Abstract

Mutations in CAPN3 gene cause limb-girdle muscular dystrophy type 2A (LGMD2A) characterized by muscle wasting and progressive degeneration of scapular and pelvic musculature. Since CAPN3 knockout mice (C3KO) display features of muscle pathology similar to those features observed in the earliest-stage or preclinical LGMD2A patients, gene expression profiling analysis in C3KO mice was performed to gain insight into mechanisms of disease. Two different comparisons were carried out in order to determine, first, the differential gene expression between wild-type (WT) and C3KO soleus and, second, to identify the transcripts differentially expressed in aging muscles of WT and C3KO mice. The up/downregulation of two genes, important for normal muscle function, was identified in C3KO mice: the Ky gene, encoding a protease implicated in muscle development, and Park2 gene encoding an E3 ubiquitin ligase (parkin). The Ky gene was downregulated in C3KO muscles suggesting that Ky protease may play a complementary role in regulating muscle cytoskeleton homeostasis in response to changes in muscle activity. Park2 was upregulated in the aged WT muscles but not in C3KO muscles. Taking into account the known functions of parkin E3 ligase, it is possible that it plays a role in ubiquitination and degradation of atrophy-specific and damaged proteins that are necessary to avoid cellular toxicity and a cellular stress response in aging muscles.

Emerging role for regulated in development and DNA damage 1 (REDD1) in the regulation of skeletal muscle metabolism

“…For example, microarray analysis of gene expression in three models of genetic muscle atrophy indicate a consistent reduction in REDD2 regardless of the model (88), and REDD2 protein content was decreased in the soleus from CAPN3 knockout mice which causes limb-girdle muscular dystrophy type 2A (61). However, mTORC1 signaling and the rate of muscle protein synthesis per se were not directly determined in these studies, and it is possible that muscle protein synthesis in these models may actually be increased, a somewhat counter- intuitive response similar to that observed in denervationinduced muscle atrophy (21).…”

Frizzled related protein deficiency impairs muscle strength, gait and calpain 3 levels

“…Among the selected genes deregulated in C3KO mice [25] the Ky gene showed expression changes in Frzb −/− mice. Its protease activity targets different proteins and its absence could disrupt muscle cytoskeleton homeostasis [73].…”

“…We then focused on genes that are differentially expressed in Capn3 −/− mice compared to wild-type mice [25]. Park2 expression was on average 17.93% higher in Frzb −/− mice compared to wild-types [(95%CI: − 8 - (Fig.…”

PLEIAD/SIMC1/C5orf25, a Novel Autolysis Regulator for a Skeletal-Muscle-Specific Calpain, CAPN3, Scaffolds a CAPN3 Substrate, CTBP1

“…9 To examine the consequences of altering the modulating functions of CAPN3 in skm, we have generated several different mouse limb-girdle muscular dystrophy type 2A models, including knockout mice ( Capn3 −/− ), which lack the full-length CAPN3 protein 10–17 ; knockin mice ( Capn3 CS/CS ) in which CAPN3 is replaced by a protease-inactive mutant CAPN3:C129S (CAPN3:CS) 18,19 ; and transgenic mice in which CAPN3:CS is overexpressed. 20 Analyses of these models have shown that CAPN3 has different cellular functions depending on the subcellular compartment in which it is located.…”