Green tea extract decreases muscle pathology and NF-κB immunostaining in regenerating muscle fibers of mdx mice

Abstract

BACKGROUND & AIMS Duchenne muscular dystrophy is a debilitating genetic disorder characterized by severe muscle wasting and early death in afflicted boys. The primary cause of this disease is mutations in the dystrophin gene resulting in massive muscle degeneration and inflammation. The purpose of this study was to determine if dystrophic muscle pathology and inflammation were decreased by pre-natal and early dietary intervention with green tea extract. METHODS Mdx breeder mice and pups were fed diets containing 0.25% or 0.5% green tea extract and compared to untreated mdx and C57BL/6J mice. Serum creatine kinase was assessed as a systemic indicator of muscle damage. Quantitative histopathological and immunohistochemical techniques were used to determine muscle pathology, macrophage infiltration, and NF-κB localization. RESULTS Early treatment of mdx mice with green tea extract significantly decreased serum creatine kinase by ~85% at age 42 days (P≤0.05). In these mice, the area of normal fiber morphology was increased by as much as ~32% (P≤0.05). The primary histopathological change was a ~21% decrease in the area of regenerating fibers (P≤0.05). NF-κB staining in regenerating muscle fibers was also significantly decreased in green tea extract-treated mdx mice when compared to untreated mdx mice. CONCLUSION Early treatment with green tea extract decreases dystrophic muscle pathology potentially by regulating NF-κB activity in regenerating muscle fibers.

Sulforaphane Attenuates Muscle Inflammation in Dystrophin-deficient mdx Mice via NF-E2-related Factor 2 (Nrf2)-mediated Inhibition of NF-κB Signaling Pathway

“…Pathway-Activation of the NF-B signaling pathway has been shown to be central to the pathophysiology of the muscular inflammatory response in patients with DMD (27,28). To investigate the mechanism of SFN-induced Nrf2 activation in amelioration of muscular inflammation, we examined the protein expression of NF-B(p65), p-IKK-␣/IKK-␣, p-IKK-␤/ IKK-␤, and p-IB-␣/IB-␣ as well as gene expression of NF-B(p65), IL-1␤, and IL-6.…”

(−)-Epigallocatechin-3-gallate (EGCG) attenuates functional deficits and morphological alterations by diminishing apoptotic gene overexpression in skeletal muscles after sciatic nerve crush injury

“…However, the improvements were slightly less than those observed previously for subcutaneous injection (5 weeks a daily average of 3 or 6 mg/kg EGCG) started immediately after birth (Nakae et al 2012). Recent studies have demonstrated that early treatment of mdx mice with GTE potentially decreases dystrophic muscle histopathology by regulating NF-κB activity in regenerating muscle fibers (Evans et al 2010). Furthermore, EGCG attenuates skeletal muscle leukocytic infiltration and downregulates tumor-induced NF-κB and E3-ligases in the cachexia muscle-wasting syndrome , thus utilizing the anti-inflammatory property of green tea polyphenols.…”

“…Diet supplementation of dystrophic mdx(5Cv) mice with GTP or EGCG protected muscle against the first massive wave of necrosis and stimulated muscle adaptation toward a stronger and more resistant phenotype (Dorchies et al 2006). Early treatment with GTP decreases dystrophic muscle pathology potentially by regulating NF-kappaB activity in regenerating muscle fibers and increasing normal fiber morphology (Evans et al 2010) as well as improvement of muscle function (Call et al 2008;Nakae et al 2008). Wang and his co-investigators have shown that EGCG is a potent preventive against cachexia, also known as wasting syndrome with notably skeletal muscle atrophy.…”

Pharmacologically Targeting the Primary Defect and Downstream Pathology in Duchenne Muscular Dystrophy

“…These benefits could be attributed to a reduction in ROS. Consistent dramatic reductions in CK were reported, even after exercise [423,424], and one study reported restoration to wild type levels following eight weeks of subcutaneous injections from birth [422]. In addition to a reduction in ROSmediated NF-B activation, it has also been suggested that GTE/EGCG can also act directly by blocking IKK activation and inhibiting ERK, Akt, P13k/Akt, implicating a direct role in modulation of the inflammatory, regenerative and fibrotic responses in DMD [425][426][427][428] (these signalling pathways are also described in sections 2.2, 3.4, 3.7 and 3.8).…”

“…The therapeutic benefits associated with very early (pregnant mothers are often treated) administration of green tea extract (GTE/EGCG) to the mdx mouse included improved histology, decreased necrosis, and improved muscle function and endurance after only weeks of treatment [420][421][422][423][424]. These benefits could be attributed to a reduction in ROS.…”