Duchenne muscular dystrophy (DMD) is a genetic disorder characterized by progressive muscle degeneration and weakness due to the alterations of a protein called dystrophin that helps keep muscle cells intact. Weakness related to DMD selectively affects the limb muscles close to the trunk before the ones far from it; the legs are affected before the arms. Growth velocity with DMD is typically slower than normal in the first years of life, leading to short stature. In a new study, researchers from McMaster University demonstrated the potential of a molecule that may help overcome some of the symptoms of DMD. The molecule promotes the activity of AMP-activated protein kinase (AMPK), an important fuel-sensing enzyme that is present in all mammalian cells.

The findings are published in The FASEB Journal in an article titled, “Acute, next-generation AMPK activation initiates a disease-resistant gene expression program in dystrophic skeletal muscle.”

The researchers utilized a next-generation oral AMPK agonist called MK-8722 and showed that when given as a single dose to mice with muscular dystrophy, it triggered signaling pathways associated with improved muscle health.

“DMD is a life-limiting neuromuscular disorder characterized by muscle weakness and wasting,” wrote the researchers. “Previous proof-of-concept studies demonstrate that the dystrophic phenotype can be mitigated with the pharmacological stimulation of AMPK. However, first-generation AMPK activators have failed to translate from bench to bedside due to either their lack of potency or toxic, off-target effects. The identification of safe and efficacious molecules that stimulate AMPK in dystrophic muscle is of particular importance as it may broaden the therapeutic landscape for DMD patients regardless of their specific dystrophin mutation. Here, we demonstrate that a single dose of the next generation, orally-bioactive AMPK agonist MK-8722 (MK) to mdx mice evoked skeletal muscle AMPK and extensive downstream stimulation within 12 h post-treatment.”

Previous research has shown that stimulating AMPK can mitigate the dystrophy—or wasting—of muscles, but AMPK activators have failed to reach the clinic due to either their lack of potency or toxic off-target effects.

“Our work highlights the therapeutic potential of this novel class of AMPK activators in DMD, as well as in other neuromuscular diseases,” said lead author Sean Ng, PhD candidate at McMaster University. “We hope that these findings can be extended to other novel AMPK agonists that are currently being investigated in ongoing clinical trials. If so, repositioning these therapies may pose as a cost-effective and efficacious method for the treatment of DMD regardless of the specific disease-causing mutation.”

Further studies are needed to test the chronic administration of such next-generation AMPK activators in dystrophic animals to further examine their safety and effectiveness.

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