Anti-inflammatory drugs for Duchenne muscular dystrophy: focus on skeletal muscle-releasing factors

Abstract

Duchenne muscular dystrophy (DMD), an incurable and a progressive muscle wasting disease, is caused by the absence of dystrophin protein, leading to recurrent muscle fiber damage during contraction. The inflammatory response to fiber damage is a compelling candidate mechanism for disease exacerbation. The only established pharmacological treatment for DMD is corticosteroids to suppress muscle inflammation, however this treatment is limited by its insufficient therapeutic efficacy and considerable side effects. Recent reports show the therapeutic potential of inhibiting or enhancing pro- or anti-inflammatory factors released from DMD skeletal muscles, resulting in significant recovery from muscle atrophy and dysfunction. We discuss and review the recent findings of DMD inflammation and opportunities for drug development targeting specific releasing factors from skeletal muscles. It has been speculated that nonsteroidal anti-inflammatory drugs targeting specific inflammatory factors are more effective and have less side effects for DMD compared with steroidal drugs. For example, calcium channels, reactive oxygen species, and nuclear factor-κB signaling factors are the most promising targets as master regulators of inflammatory response in DMD skeletal muscles. If they are combined with an oligonucleotide-based exon skipping therapy to restore dystrophin expression, the anti-inflammatory drug therapies may address the present therapeutic limitation of low efficiency for DMD.

Keywords:

• calcium channels
• ryanodine receptor 1
• exon skipping
• NF-κB
• myokine
• ROS

Acknowledgments

This work was supported by the Japan Society for the Promotion of Science Grant-in-Aid for Research Activity Start-up (grant to YA) (number 15H06883) and the Japan Agency for Medical Research and Development (AMED) (16ek0109154h0002 and 16am0301021h0002). We are grateful to Dr Urs T Ruegg and Dr Takashi Saito for their insightful comments and suggestions.

Disclosure

The authors report no conflicts of interest in this work.