UCLA researchers in the Department of Neurology have developed a novel mouse model for limb girdle muscular dystrophy, a disorder that causes muscle weakness in the limbs and hip area.
BACKGROUND: Limb-Girdle Muscular Dystrophy Type 2A (LGMDR1) is a genetic neuromuscular disorder characterized by progressive muscle weakness, primarily affecting muscles around the shoulders and hips. This weakness leads to difficulties in tasks like lifting arms, climbing stairs, and getting up from a seated position. Individuals with LGMDR1 exhibit gait abnormalities, a progressive loss of muscle mass, and a visibly thin appearance in the limbs. LGMDR1 is primarily caused by mutations in the CAPN3 gene, which encodes the calpain-3 protein. Calpain-3 belongs to a large family of proteases and is expressed specifically in skeletal muscle and plays an important role in maintaining the structure and function of muscle cells. Mutations in the CAPN3 gene lead to a deficiency or dysfunction of calpain-3, disrupting the normal cellular processes in muscle tissue and resulting in the degeneration of muscle fibers. Calpain-3 plays a crucial role in maintaining muscle structure by regulating the cytoskeleton and participating in controlled protein degradation. The use of genetically modified mouse models of LGMDR1 where the CAPN3 gene is inactivated canvastly contributed to our understanding of the biological function of calpain-3 in muscle remodeling.
INNOVATION: The laboratory of Dr. Melissa Spencer developed a CAPN3 knockout (KO) mouse model to better understand the functional role of calpain-3 in LGMDR1. The Spencer Lab found that histology from CAPN3 KO mice showed similar features to those observed in human LGMDR1, such as abnormal sarcomere organization and presence of apoptotic nuclei outside the muscle fibers. Additionally, researchers observed impaired interactions between calpain-3 and titin, the largest known protein in the body involved in muscle contraction and elasticity. In sum, the CAPN3 KO mouse model developed at UCLA demonstrates the deficits seen in a muscular disorder like LGMDR1, and will be an important experimental tool for uncovering additional mechanisms and pathogeneses underlying neuromuscular disorders.
POTENTIAL APPLICATIONS:
- LGMDR1 disorder mechanism understanding (molecular pathological features)
- Biomarker discovery
- Preclinical model for therapeutic development of neuromuscular disorders
ADVANTAGES:
- Specific gene inactivation
- Causal understanding between gene inactivation and resulting phenotype
- Cost-effective life science research tool
DEVELOPMENT-TO-DATE: in-vivo and in-vitro studies
RELATED PAPER (from the inventors only): Kramerova, I., Kudryashova, E., Tidball, J. G., and Spencer, M. J. (2004). Null mutation of calpain 3 (p94) in mice causes abnormal sarcomere formation in vivo and in vitro. Human Molecular Genetics, 13(13), 1373-1388.
KEYWORDS: mouse model, limb girdle muscular dystrophy, LGMDR1, calpain-3, CAPN3, neuromuscular disorder