Restorative potential of (−)-epicatechin in a rat model of Gulf War illness muscle atrophy and fatigue

Abstract

We examined in a rat model of Gulf War illness (GWI), the potential of (−)-epicatechin (Epi) to reverse skeletal muscle (SkM) atrophy and dysfunction, decrease mediators of inflammation and normalize metabolic perturbations. Male Wistar rats (n = 15) were provided orally with pyridostigmine bromide (PB) 1.3 mg/kg/day, permethrin (PM) 0.13 mg/kg/day (skin), DEET 40 mg/kg/day (skin) and were physically restrained for 5 min/day for 3 weeks. A one-week period ensued to fully develop the GWI-like profile followed by 2 weeks of either Epi treatment at 1 mg/kg/day by gavage (n = 8) or water (n = 7) for controls. A normal, control group (n = 15) was given vehicle and not restrained. At 6 weeks, animals were subjected to treadmill and limb strength testing followed by euthanasia. SkM and blood sampling was used for histological, biochemical and plasma pro-inflammatory cytokine and metabolomics assessments. GWI animals developed an intoxication profile characterized SkM atrophy and loss of function accompanied by increases in modulators of muscle atrophy, degradation markers and plasma pro-inflammatory cytokine levels. Treatment of GWI animals with Epi yielded either a significant partial or full normalization of the above stated indicators relative to normal controls. Plasma metabolomics revealed that metabolites linked to inflammation and SkM waste pathways were dysregulated in the GWI group whereas Epi, attenuated such changes. In conclusion, in a rat model of GWI, Epi partially reverses detrimental changes in SkM structure including modulators of atrophy, inflammation and select plasma metabolites yielding improved function.

Selective Inhibition of Soluble TNF Attenuates Hippocampal Neuroinflammation and PSD-95 Expression to Improve Neurological Functions in a Rat Model of Gulf War Illness

“…An intriguing question that arises from these studies is how using XPro1595 to neutralize solTNF may be reversing DFP-induced impairments, and thus is there any clinical relevance? While rodent studies show increased hippocampal and serum TNF expression acutely and 6 weeks following GWI induction (11) (94), studies on Veterans in the chronic environment with diagnosed GWI show baseline serum TNF levels (95) (96), and our studies also show no difference in TNFR1 protein expression chronically following DFP exposure. However, even small variances in TNF expression that may be difficult to detect have been shown to drive pathological changes (29).…”

New Trends to Treat Muscular Atrophy: A Systematic Review of Epicatechin

“…A reduced sample size was identified [ 37 , 42 , 43 ]; brief time assessment [ 40 ]; the data of the participant’s diet were not collected [ 41 , 42 ]; absence of an evaluation of EC consumption in different periods [ 37 , 38 , 39 , 40 , 41 , 42 , 45 , 46 , 48 , 49 , 50 , 51 , 54 , 55 , 57 , 58 , 59 , 60 , 61 ]; only one dose was studied [ 37 , 38 , 39 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 58 , 60 , 61 ]; absence of EC plasma concentrations [ 39 , 40 , 42 ,…”

“…Epicatechin supplementation has exhibited promising clinical applicability in the regeneration of muscle tissue [ 6 , 23 , 28 , 29 , 33 , 34 , 37 , 38 , 39 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 ]. Thus, this systematic review intended to evaluate the effects of EC as dietary supplementation on skeletal muscle atrophy.…”

“…In skeletal muscle, epicatechin suppresses the expression of atrogenes induced by FoxO [ 2 , 49 , 51 , 53 , 54 ] and improves muscle performance when combined with physical activity [ 52 , 54 ]. In addition, the major protein synthesis pathway (AKT/mTORC1) [ 2 , 30 , 31 , 32 , 51 , 55 ] and specific tissue markers that control myogenic differentiation, such as Myf5 [ 9 , 34 , 37 , 42 , 48 ], MyoD [ 48 , 56 , 58 ], and myogenin [ 48 , 56 , 57 , 58 , 60 ], were stimulated by epicatechin.…”

Restorative effects of (+)-epicatechin in a rodent model of aging induced muscle atrophy: underlying mechanisms

“…18 In a rat model of SkM dysfunction mimicking Gulf War illness, (−)-epicatechin reverses SkM atrophy and increases exercise capacity while decreasing TNF-α levels. 19 Recently, we characterized the epimer (+)-epicatechin (+Epi) as 10 fold more potent vs. (−)-epicatechin in stimulating neurogenesis 20 but have not explored its SkM effects in the setting of aging.…”