Mitochondria a likely treatment target to stop MD progression
Dystrophic disease 'vanishes' in mouse model of the disease, researcher said
Blocking the activation of a channel in mitochondria, the cells’ powerhouses, may be a promising way to stop muscular dystrophy (MD) progression in a mouse model of the disease.
“We have isolated the primary disease-causing component of muscular dystrophy to the mitochondrial permeability pore,” Jeffery Molkentin, PhD, co-executive director of the Heart Institute at Cincinnati Children’s Hospital, and the study’s senior author, said in a press release. “If we prevent this pore from functioning, dystrophic disease in the mouse models we studied almost completely vanishes. We see the protection lasting past one year of life in the mouse, which translates to about 40 years of life for a human.”
The findings point to a “previously unrecognized therapeutic approach in MD” and related diseases, the researchers wrote in “ANT-dependent MPTP underlies necrotic myofiber death in muscular dystrophy,” which was published in Sciences Advances.
A proper balance of calcium inside muscle fibers is critical for muscle contraction and relaxation, energy metabolism, and muscle repair. A high calcium influx into mitochondria induces their swelling and rupture, triggering the death of muscle fibers. This process is known to play a role in multiple conditions, including MD.
The mitochondrial permeability transition pore (MPTP) works as a channel in the mitochondria’s inner membrane, opening in response to high calcium and oxidative stress, which leads to cell death. Oxidative stress occurs when the production of toxic molecules called reactive oxygen species outweighs antioxidant defenses in the body.
The partners that mediate MPTP formation aren’t fully known. Previous studies suggested MPTP has two components — the ANT family of proteins and an unknown component that requires activating cyclophilin D (CypD).
A new therapeutic strategy for targeting MD progression?
A research team led by Cincinnati Children’s scientists assessed whether these two components regulate the mitochondria-mediated cell death in MD and deleted two genes in a mouse model of limb-girdle MD — Slc25a4 and Ppif. The Slc25a4 gene codes for the ANT1 protein and Ppif codes for CypD.
Deleting Slc25a4 desensitized MPTP activation, as it did with the loss of Ppif, and improved mitochondrial function in muscle.
The researchers then analyzed the level of degeneration in both leg muscles and the diaphragm, a key muscle in breathing, and found muscle degeneration was markedly reduced in mice lacking Slc25a4. Deleting either Slc25a4 or Ppif improved muscle function, but not to the level of healthy mice, which the investigators attributed to metabolic dysfunction.
When both Slc25a4 and Ppif were deleted, substantially improved mitochondrial structure, enhanced metabolic function, limited muscle cell death, and lowered levels of a muscle damage marker resulted. The distance mice could run on a treadmill and the force exerted by the tibialis anterior, a muscle in the lower leg, were also normalized.
“We found direct evidence that these genes produce required components that govern cell death, which opens a previously unrecognized pathway for potentially treating MDs and other necrotic diseases,” Molkentin said. Necrosis is a form of cell death that occurs due to injuries, infections or diseases.
The findings suggest the possibility of developing new therapeutic avenues for muscular dystrophies, although further studies are required.
A medication called cyclosporin A can block the CypD protein, however its prolonged use at high doses is linked with significant side effects. No existing medications target ANT1.
“If a nontoxic ANT inhibitor can be identified, that also can target the mitochondrial pore, our results suggest that combined treatment with low dosages of a CypD inhibitor could be a novel therapeutic strategy,” Molkentin said. “Such a treatment could provide benefits independently or in combination with other gene therapies.” Whether this approach could also confer benefits against damage to the heart or other organs remains to be determined.