Duchenne muscular dystrophy (DMD) results from the loss of dystrophin, a protein located beneath the membrane of muscle cells. Its absence weakens this membrane and causes the progressive degeneration of skeletal, smooth, and cardiac muscle. At present, no curative treatment is available, and patients die on average around the age of thirty, now mainly as a result of dilated cardiomyopathy and heart failure. Preserving cardiac muscle therefore represents a central therapeutic challenge. Two major abnormalities characterize the disease: a dysregulation of calcium homeostasis, linked to Ca²⁺ influx associated with hyperactivation of ryanodine receptors, and a muscular deficit in nicotinamide adenine dinucleotide (NAD⁺), a molecule essential to numerous cellular processes and to cell survival.
The authors focused on the enzyme CD38, which consumes NAD⁺ to produce modulators of calcium channels. By deleting the gene encoding CD38 in the mdx mouse, a model of DMD, the team observed a complete restoration of cardiac function and structure, accompanied by improved skeletal muscle performance. The limb muscles and diaphragm benefited from a reduction in cycles of fibrosis and regeneration as well as in markers of inflammation and senescence, suggesting prevention of cellular damage and necrosis. Muscular NAD⁺ levels were fully restored, while the concentrations of the two main CD38 products, nicotinamide and ADP-ribose, decreased in the heart, diaphragm, and limbs.
The pathological spontaneous calcium activity of cardiomyocytes was furthermore reduced in CD38-deficient mdx mice. This correction was also found in human myotubes derived from patients with DMD and treated with isatuximab, an anti-CD38 monoclonal antibody. Finally, the administration of CD38 inhibitors to mdx mice and to mice doubly deficient in utrophin and dystrophin (mdx/utr⁻/⁻) improved skeletal muscle performance, confirming the value of pharmacologically targeting the enzyme. Calcium imaging experiments, histological assessment of fibrosis and immune infiltration, and functional exercise tests all supported these observations.
This work establishes that CD38 actively contributes to the pathophysiology of DMD by acting simultaneously on the two deleterious parameters of calcium dysregulation and NAD⁺ deficiency. The authors emphasize that a selective anti-CD38 therapy, like isatuximab already approved for multiple myeloma, would offer the advantages of short-term applicability, a low risk of immune rejection, and a reduced tendency toward tumorigenicity. They thus propose CD38 as a relevant therapeutic target for patients with DMD, in particular for its dilated cardiomyopathy.