Abstract
Limb-girdle muscular dystrophy recessive 1 (LGMDR1), previously known as LGMD2A, is a rare disease caused by mutations in the CAPN3 gene. It is characterized by progressive weakness of shoulder, pelvic, and proximal limb muscles that usually appears in children and young adults and results in loss of ambulation within 20 years after disease onset in most patients. The pathophysiological mechanisms involved in LGMDR1 remain mostly unknown, and to date, there is no effective treatment for this disease. Here, we review clinical and experimental evidence suggesting that dysregulation of Ca2+ homeostasis in the skeletal muscle is a significant underlying event in this muscular dystrophy. We also review and discuss specific clinical features of LGMDR1, CAPN3 functions, novel putative targets for therapeutic strategies, and current approaches aiming to treat LGMDR1. These novel approaches may be clinically relevant not only for LGMDR1 but also for other muscular dystrophies with secondary calpainopathy or with abnormal Ca2+ homeostasis, such as LGMD2B/LGMDR2 or sporadic inclusion body myositis.
Highlights
Ca2+ plays a vital role in a wide range of cellular processes such as gene transcription, membrane resealing, secretion, neurotransmission, as well as cell differentiation, proliferation, or survival [1,2]
Several mouse models of Limb-girdle muscular dystrophy recessive 1 (LGMDR1) have been used to understand the pathogenic mechanisms resulting from calpain 3 (CAPN3) deficiency
We have reviewed different participants disrupted in LGMDR1 that regulate Ca2+ homeostasis
Summary
Ca2+ plays a vital role in a wide range of cellular processes such as gene transcription, membrane resealing, secretion, neurotransmission, as well as cell differentiation, proliferation, or survival [1,2]. CaMK pathway is involved in the regulation of contraction-induced Ca2+ handling, and mitochondrial biogenesis It regulates gene expression in skeletal muscle, promoting the slow to fast fiber shift [27]. ECC triggers transient Ca2+ increases in the mitochondrial matrix, which are essential to promote mitochondrial metabolism and ATP synthesis This is required to balance the ATP consumption of actomyosin cross-bridge cycling and SERCA pumps during contraction and relaxation, respectively [37]. Myosin-Va, a Ca2+ sensor molecule, may regulate mitochondria-bound molecular motors allowing mitochondrial movements along cytoskeletal fibers and controlling the distribution of mitochondria to enhance Ca2+ buffering and ATP production in regions with high cytosolic [Ca2+] [36]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
