A new paper, “CaMKIIβ Signaling drives expression of metabolic and stress response genes in skeletal muscle, and its loss contributes to the LGMDR1 phenotype,” was recently published in the journal Human Molecular Genetics. It was authored by a multi-institutional group led by Dr. Melissa Spencer, C3 Scientific Advisory Board Chair and Professor of Neurology and Director of the Neuromuscular Program at UCLA.
This project was funded, in part, by a grant from Coalition to Cure Calpain 3
LGMD2A/R1 is caused by mutations in the CAPN3 gene which cause the protein calpain 3 to be either missing or non-functional. For decades, researchers have been trying to understand the reasons why missing or non-functional calpain 3 leads to muscle weakness. This study focuses on a specific cellular “switch” called CaMKIIβ. In healthy muscles, CaMKIIβ is turned on in response to endurance exercise, which leads to changes in energy production and metabolism.
Researchers found that in mice that lack calpain 3, CaMKIIβ signaling is dampened and associated with a drop in the activity of genes tied to energy production and metabolism. Muscle biopsies from LGMD2A/R1 patients showed similar changes compared to controls.
To see if fixing CaMKIIβ signaling could potentially help patients, researchers artificially increased the activity by expressing an active form of CaMKIIβ in calpain 3-null mice. They found it improved muscle function and metabolism.