Abstract
Growing evidence suggests acute skeletal muscle wasting is a key factor affecting nutritional support and prognosis in critical patients. Previously, plenty of studies of muscle wasting focused on the peripheral pathway, little was known about the central role. We tested the hypothesis whether central inflammatory pathway and neuropeptides were involved in the process. In lipopolysaccharide (LPS) treated rats, hypothalamic NF-κB pathway and inflammation were highly activated, which was accompanied with severe muscle wasting. Central inhibition of nuclear factor kappa-B (NF-κB) pathway activation by infusion of an inhibitor (PS1145) can efficiently reduce muscle wasting as well as attenuate hypothalamic neuropeptides alteration. Furthermore, knockdown the expression of anorexigenic neuropeptide proopiomelanocortin (POMC) expression with a lentiviral vector containing shRNA can significantly alleviate LPS-induced muscle wasting, whereas hypothalamic inflammation or NF-κB pathway was barely affected. Taken together, these results suggest activation of hypothalamic POMC is pivotal for acute muscle wasting caused by endotoxemia. Neuropeptide POMC expression may have mediated the contribution of hypothalamic inflammation to peripheral muscle wasting. Pharmaceuticals with the ability of inhibiting hypothalamic NF-κB pathway or POMC activation may have a therapeutic potential for acute muscle wasting and nutritional therapy in septic patients.
Highlights
Central inflammation is both essential and sufficient to induce muscle atrophy[14,15]
We firstly demonstrated that inhibiting the activation of central IKKβ/NF-κB pathway could reduce the expression of hypothalamic inflammation and neuropeptides, and more importantly, peripheral skeletal muscle wasting induced by LPS was largely attenuated
Further experiment shown that knocking down the expression of a key neuropeptide, POMC, by a central lentiviral approach can efficiently ameliorate muscle wasting, without significant effect on central inflammation and other neuropeptides
Summary
Central inflammation is both essential and sufficient to induce muscle atrophy[14,15]. AgRP acts as an antagonist of MC4R, and central administration of AgRP could ameliorate muscle wasting and systemic inflammation caused by chronic kidney disease[17]. Both the neurons are subjected to proinflammatory cytokines and circulating molecules, such as insulin and leptin, to regulate energy balances[10,12]. IKKβ/NF-κB is a pivotal regulator of the expression of genes related inflammation and innate immunity[18]. Inflammatory stimuli activate the IκB kinase(IKK)complex, which phosphorylates IκB, leading to its degradation. This will facilitates translocation of NF-κBto the nucleus, regulating the transcription of genes. Since the reduced appetite and acute wasting were presented by critical patients simultaneously, we hypothesized that hypothalamic NF-κBpathway and neuropeptides were involved in the regulation of acute skeletal muscle wasting induced by sepsis, and tested whether inhibiting hypothalamic NF-κB activation or knocking down certain neuropeptide can mitigate the detrimental process
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