Ficus carica L. Attenuates Denervated Skeletal Muscle Atrophy via PPARα/NF-κB Pathway

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.

Electrical Stimulation Attenuates Disuse Muscular Atrophy by Modulating Endoplasmic Reticulum Stress-induced Parkin-dependent Mitophagy

“…Loss of wet weight is one of the most intuitive representations of muscle atrophy [29,30]. Biological ndings in this study showed that the wet weight of rectus femoris muscles decreased with the prolonging of immobilization time.…”

ROS-activated CXCR2+ neutrophils recruited by CXCL1 delay denervated skeletal muscle atrophy and undergo P53-mediated apoptosis

“…Previous basic and clinical studies have suggested that neutrophils are major participants in early inflammatory processes and can be swiftly deployed to sites of damage or infection [45][46][47] . However, to date, only a few inflammation-related molecules have been found in denervated muscle 48,49 . Although denervated muscle cells themselves are not directly harmed or infected and no local pathogens attract neutrophils during denervation, we demonstrated the dynamic changes in the number of neutrophils in the circulation and in muscle over time after denervation.…”

Identification of Potentially Related Genes and Mechanisms Involved in Skeletal Muscle Atrophy Induced by Excessive Exercise in Zebrafish

“…Although p53 signaling can respond to cell pressure and regulate autophagy, apoptosis, and the cell cycle to maintain cell homeostasis, dysfunctional p53 signaling is associated with a variety of diseases. Increased expression of p53 and its target genes has been previously observed in muscle atrophy models of aging [ 46 ], muscle denervation [ 47 ], and Huntington′s disease [ 48 ]. Therefore, we speculate that the starvation and oxidative stress induced by excessive exercise lead to ER pressure and activate p53 signaling.…”