Promising study identifies compound that improves muscle in LGMD2A/R1 mice

A new publication from Dr. Melissa Spencer’s laboratory at the University of California Los Angeles identifies a compound that mimics the effects of exercise in a mouse model of limb girdle muscular dystrophy type 2A (LGMD2A/R1). These studies may point the way to similar compounds that will benefit people living with muscular dystrophy.   

Mutations in the gene CAPN3 that are associated with LGMD2A/R1 lead to loss of function of the protein Calpain 3. Dr. Spencer and colleagues have previously demonstrated that loss of Calpain 3 activity is associated with improper signaling of a chemical messenger called CaMK. Since CaMK is known to play a critical role in muscle’s response to exercise, the researchers believe that altered CaMK messaging is at the center of LGMD2A/R1 symptoms. Therefore, they set out to test the hypothesis that ‘fixing’ the state of CaMK will improve Calpain 3-deficient muscle. The researchers used lab-grown muscle cells to screen over 2,000 compounds in order to find ones that restore CaMK. The most promising candidates were then tested in a mouse model of LGMD2A/R1. These mice, like LGMD2A/R1 patients, have a mutation in the gene for Calpain 3 that leads to muscle weakness.

The cell screen identified a chemical called AMBMP which activates CaMK messaging. When administered to mice, muscle structure improved and running ability was increased compared to animals given a placebo. These results suggest that targeting CaMK or a related protein could be beneficial for LGMD2A/R1 patients. AMBMP was only tested in cells and mice and has not been tested in humans or approved by the Food and Drug Administration as safe and effective for use in humans. The researchers are currently producing similar compounds that they anticipate will be suitable for human use.

Dr. Spencer is a C3 grant recipient and Chair of our Scientific Advisory Board. We congratulate her and her colleagues on this important work.

Full text of the publication can be accessed on the Cell Reports Medicine website.