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Caffeic acid alleviates skeletal muscle atrophy in 5/6 nephrectomy rats through the TLR4/MYD88/NF-kB pathway
Abstract:
Skeletal muscle atrophy is a common complication of chronic kidney disease (CKD) that affects the quality of life and prognosis of patients. We aimed to investigate the effects and mechanisms of caffeic acid (CA), a natural phenolic compound, on skeletal muscle atrophy in CKD rats. Male Sprague-Dawley rats underwent 5/6 nephrectomy (NPM) and were treated with CA (20, 40, or 80 mg/kg/day) for 10 weeks. The body and muscle weights, renal function, hemoglobin, and albumin were measured. The histological, molecular, and biochemical changes in skeletal muscles were evaluated using hematoxylin-eosin staining, quantitative real-time PCR, malondialdehyde/catalase/superoxide dismutase/glutathione level detection, and enzyme-linked immunosorbent assay. Western blotting and network pharmacology were applied to identify the potential targets and pathways of CA, CKD, and muscle atrophy. The results showed that CA significantly improved NPM-induced muscle-catabolic effects, reduced the expression of muscle atrophy-related proteins (muscle atrophy F-box and muscle RING finger 1) and proinflammatory cytokines (interleukin [IL]-6, tumor necrosis factor-alpha, and IL-1β), and attenuated muscle oxidative stress. Network pharmacology revealed that CA modulated the response to oxidative stress and nuclear factor kappa B (NF-κB) signaling pathway and that Toll-like receptor 4 (TLR4) was a key target. In vivo experiment confirmed that CA inhibited the TLR4/myeloid differentiation primary response 88 (MYD88)/NF-kB signaling pathway, reduced muscle iron levels, and restored glutathione peroxidase 4 activity, thereby alleviating ferroptosis and inflammation in skeletal muscles. Thus, CA might be a promising therapeutic agent for preventing and treating skeletal muscle atrophy in CKD by modulating the TLR4/MYD88/NF-κB pathway and ferroptosis.
Insights
Caffeic acid (CA) combats skeletal muscle atrophy in chronic kidney disease (CKD) by reducing inflammation and oxidative stress. This natural compound targets the TLR4/MYD88/NF-kB pathway, alleviating ferroptosis and improving muscle health in CKD rats.
Area of Science:
- Nephrology
- Molecular Biology
- Biochemistry
Background:
- Skeletal muscle atrophy is a significant complication in chronic kidney disease (CKD), negatively impacting patient prognosis and quality of life.
- Understanding the molecular mechanisms underlying CKD-associated muscle wasting is crucial for developing effective therapeutic strategies.
Purpose of the Study:
- To investigate the therapeutic effects of caffeic acid (CA), a natural phenolic compound, on skeletal muscle atrophy in a rat model of CKD.
- To elucidate the underlying molecular mechanisms, including key signaling pathways and targets, through which CA exerts its protective effects.
Main Methods:
- A 5/6 nephrectomy (NPM) rat model was established to induce CKD; rats were subsequently treated with varying doses of CA.
- Evaluated body/muscle weights, renal function, and biochemical markers; assessed skeletal muscle via histology, gene expression (qPCR), protein analysis (Western blotting), and oxidative stress assays.
- Network pharmacology was employed to predict CA targets and pathways, with subsequent in vivo validation of the Toll-like receptor 4 (TLR4)/myeloid differentiation primary response 88 (MYD88)/nuclear factor kappa B (NF-κB) pathway.
Main Results:
- CA treatment significantly ameliorated NPM-induced muscle atrophy, reducing the expression of key atrophy-related proteins (Atrogin-1, MuRF1) and pro-inflammatory cytokines (IL-6, TNF-α, IL-1β).
- CA attenuated skeletal muscle oxidative stress and ferroptosis, evidenced by reduced malondialdehyde levels and restored glutathione peroxidase 4 activity.
- Network pharmacology and in vivo studies confirmed CA's modulation of the TLR4/MYD88/NF-κB signaling pathway, suggesting its role in inhibiting inflammation and ferroptosis.
Conclusions:
- Caffeic acid demonstrates significant potential as a therapeutic agent for mitigating skeletal muscle atrophy in the context of CKD.
- CA's protective effects are mediated through the inhibition of the TLR4/MYD88/NF-κB pathway, leading to reduced inflammation, oxidative stress, and ferroptosis in skeletal muscle.
