Abstract
Duchenne muscular dystrophy (DMD) is characterized by progressive muscle weakness and wasting due to the lack of dystrophin protein. The acute phase of DMD is characterized by muscle necrosis and increased levels of the pro-inflammatory mediator, prostaglandin D2 (PGD2). Inhibiting the production of PGD2 by inhibiting hematopoietic prostaglandin D synthase (HPGDS) may alleviate inflammation and decrease muscle necrosis. We tested our novel HPGDS inhibitor, PK007, in the mdx mouse model of DMD. Our results show that hindlimb grip strength was two-fold greater in the PK007-treated mdx group, compared to untreated mdx mice, and displayed similar muscle strength to strain control mice (C57BL/10ScSn). Histological analyses showed a decreased percentage of regenerating muscle fibers (~20% less) in tibialis anterior (TA) and gastrocnemius muscles and reduced fibrosis in the TA muscle in PK007-treated mice. Lastly, we confirmed that the DMD blood biomarker, muscle creatine kinase activity, was also reduced by ~50% in PK007-treated mdx mice. We conclude that our HPGDS inhibitor, PK007, has effectively reduced muscle inflammation and fibrosis in a DMD mdx mouse model.
Highlights
Our results show that PK007 does significantly improve the level of muscle grip during the early acute phase of Duchenne muscular dystrophy (DMD) in these mice
We show that hind limb muscles from PK007-treated mdx mice had ~20% fewer regenerating muscle fibers
20% of muscle fibers were saved from cell death during the acute phase of DMD in mdx mice, a percentage of rescue that resulted in improved muscle grip to the same levels as in strain control mice (PK007 and vehicle treated)
Summary
Duchenne muscular dystrophy (DMD) affects approximately 1 in 3500 males and is characterized by progressive muscle weakness and wasting due to the lack of dystrophin protein [1]. A deficiency in dystrophin results in the degeneration of skeletal and cardiac muscle [2,3]. Degeneration of these muscles occurs as early as four years of age in patients, with initial signs of disease being limb muscle weakness or abnormal gait [4,5]. Symptoms range from Bower’s sign, a sign that indicates muscle weakness of the proximal limb muscles, to swollen calves due to fat and fibrotic tissue build-up within the gastrocnemius muscle [3,5]
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