Cyclo His-Pro halts skeletal muscle degeneration and cardiomyopathy in murine myopathy models
Among the inherited myopathies, a group of muscular disorders characterized by structural and metabolic impairments in skeletal muscle, Duchenne muscular dystrophy (DMD) stands out for its devastating progression. Caused by the absence of functional dystrophin, DMD pathogenesis is driven by the progressive degeneration of muscle fibers, resulting in the development of inflammation and fibrosis that ultimately affect the overall muscle biomechanics. On the opposite end of the spectrum of muscle diseases, age-related sarcopenia is a common disease that affects a growing proportion of the elderly, often leading to frailty and loss of independence. Although characterized by fundamentally different pathological mechanisms, DMD and sarcopenia share the development of progressive muscle weakness and tissue inflammation. The natural compound Cyclo Histidine-Proline (CHP) has been shown to reduce inflammation and fibrosis in a number of metabolic diseases, including steatohepatitis and diabetes. We evaluate here the effects of CHP in DMD and sarcopenia. In two independent studies in the mdx mouse model of DMD, we show that CHP restored muscle contractility and force production, accompanied by a robust reduction of fibrosis and inflammation in skeletal muscle. In the mdx model, CHP furthermore prevented the development of cardiomyopathy and fibrosis in the diaphragm, the two leading causes of death for DMD patients. CHP also attenuated muscle atrophy and functional deterioration in a mouse model of age-related sarcopenia. These data in two different models of muscle dysfunction hence warrant further study of the effects of CHP in muscle pathologies in animal models and eventually in patients. Overall design: C57BL/10ScSn (BL10) and C57BL/10ScSn-Dmdmdx (mdx) male mice (The Jackson Laboratory) were housed at 22°C with free to access to water and chow diet ad libitum. After a week of adaptation, mice were divided into three groups: mdx received either CHP treatment or water (control), BL10 mice received water (control), three times per week by oral gavage. Mice were treated from week 7 to week 22 of age with CHP at a dose of 35 mg/kg or water as control. 18-month-old male C57BL6/J mice (Korea basic science institute [KBSI]) were housed in individual cages in constant temperature and humidity air-conditioning cabinet (JD-SY-02, Jungdo) at a temperature of 23 ± 3? and a humidity of 50% with a 12 hours light/dark cycle. Mice were free to access distilled water (DW) and laboratory chow diet ad libitum. Mice were divided into two groups based on equal average body weight, and DW or CHP (35mg/kg/day) was orally administered for 6 months.