Abstract
Treatment options for denervated skeletal muscle atrophy are limited, in part because the underlying molecular mechanisms are not well understood. Unlike previous transcriptomics studies conducted in rodent models of peripheral nerve injury, in the present study, we performed high-throughput sequencing with denervated atrophic biceps muscle and normal (non-denervated) sternocleidomastoid muscle samples obtained from four brachial plexus injury (BPI) patients. We also investigated whether Ficus carica L. (FCL.) extract can suppress denervated muscle atrophy in a mouse model, along with the mechanism of action. We identified 1471 genes that were differentially expressed between clinical specimens of atrophic and normal muscle, including 771 that were downregulated and 700 that were upregulated. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that the differentially expressed genes were mainly enriched in the GO terms “structural constituent of muscle,” “Z disc,” “M band,” and “striated muscle contraction,” as well as “Cell adhesion molecules,” “Glycolysis/Gluconeogenesis,” “Peroxisome proliferator-activated receptor alpha (PPARα) signaling pathway,” and “P53 signaling pathway.” In experiments using mice, the reduction in wet weight and myofiber diameter in denervated muscle was improved by FCL. extract compared to saline administration, which was accompanied by downregulation of the proinflammatory cytokines interleukin (IL)-1β and IL-6. Moreover, although both denervated groups showed increased nuclear factor (NF)-κB activation and PPARα expression, the degree of NF-κB activation was lower while PPARα and inhibitor of NF-κB IκBα expression was higher in FCL. extract-treated mice. Thus, FCL. extract suppresses denervation-induced inflammation and attenuates muscle atrophy by enhancing PPARα expression and inhibiting NF-κB activation. These findings suggest that FCL. extract has therapeutic potential for preventing denervation-induced muscle atrophy caused by peripheral nerve injury or disease.
Highlights
Peripheral nerve injury often leads to skeletal muscle atrophy, which seriously affects normal limb function and the quality of life of patients (Burns et al, 2012; Ehmsen and Höke, 2020)
To determine whether FCL. extract attenuates denervated muscle atrophy via this mechanism, we evaluated the activation of nuclear factor (NF)-κB and expression of IκBα (Figure 6)
To determine whether the attenuation of inflammation in denervated muscle by FCL. extract involves PPARα, we examined PPARA transcript and PPARα protein expression and found that both were significantly increased in Den-FCL. group mice compared to Den-saline group mice, suggesting that FCL. extract suppresses the inflammation associated with muscle denervation by promoting of PPARα expression
Summary
Peripheral nerve injury often leads to skeletal muscle atrophy, which seriously affects normal limb function and the quality of life of patients (Burns et al, 2012; Ehmsen and Höke, 2020). There are limited clinically effective treatments for reversing or delaying the process of muscle atrophy; clarifying the underlying mechanisms can lead to the development of effective therapeutic strategies. It is worth noting that these previous studies were mostly carried out using rodent models of muscle atrophy induced by sciatic nerve transection. Other than investigations on amyotrophic lateral sclerosis and spinal muscular atrophy, there have been no published microarray or RNA-seq studies to date using denervated atrophic muscle from humans (Birger et al, 2019; Onodera et al, 2020)
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