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Ficus carica L. Attenuates Denervated Skeletal Muscle Atrophy via PPAR?/NF-?B 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 (PPAR?) 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)-1? and IL-6. Moreover, although both denervated groups showed increased nuclear factor (NF)-?B activation and PPAR? expression, the degree of NF-?B activation was lower while PPAR? and inhibitor of NF-?B I?B? expression was higher in FCL. extract-treated mice. Thus, FCL. extract suppresses denervation-induced inflammation and attenuates muscle atrophy by enhancing PPAR? expression and inhibiting NF-?B activation. These findings suggest that FCL. extract has therapeutic potential for preventing denervation-induced muscle atrophy caused by peripheral nerve injury or disease.

SUBMITTER: Dai J

PROVIDER: S-EPMC7744683 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

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

Dai Junxi J Xiang Yaoxian Y Fu Da D Xu Lei L Jiang Junjian J Xu Jianguang J

Frontiers in physiology 20201203

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 <i>Ficu ...[more]

PMID: 33343385

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Project description:Although denervated muscle atrophy is common, the underlying molecular mechanism remains unelucidated. We have previously found that oxidative stress and inflammatory response may be early events that trigger denervated muscle atrophy. Isoquercitrin is a biologically active flavonoid with antioxidative and anti-inflammatory properties. The present study investigated the effect of isoquercitrin on denervated soleus muscle atrophy and its possible molecular mechanisms. We found that isoquercitrin was effective in alleviating soleus muscle mass loss following denervation in a dose-dependent manner. Isoquercitrin demonstrated the optimal protective effect at 20 mg/kg/d, which was the dose used in subsequent experiments. To further explore the protective effect of isoquercitrin on denervated soleus muscle atrophy, we analyzed muscle proteolysis via the ubiquitin-proteasome pathway, mitophagy, and muscle fiber type conversion. Isoquercitrin significantly inhibited the denervation-induced overexpression of two muscle-specific ubiquitin ligases-muscle RING finger 1 (MuRF1) and muscle atrophy F-box (MAFbx), and reduced the degradation of myosin heavy chains (MyHCs) in the target muscle. Following isoquercitrin treatment, mitochondrial vacuolation and autophagy were inhibited, as evidenced by reduced level of autophagy-related proteins (ATG7, BNIP3, LC3B, and PINK1); slow-to-fast fiber type conversion in the target muscle was delayed via triggering expression of peroxisome proliferator-activated receptor ? coactivator 1? (PGC-1?); and the production of reactive oxygen species (ROS) in the target muscle was reduced, which might be associated with the upregulation of antioxidant factors (SOD1, SOD2, NRF2, NQO1, and HO1) and the downregulation of ROS production-related factors (Nox2, Nox4, and DUOX1). Furthermore, isoquercitrin treatment reduced the levels of inflammatory factors-interleukin (IL)-1?, IL-6, and tumor necrosis factor-? (TNF-?)-in the target muscle and inactivated the JAK/STAT3 signaling pathway. Overall, isoquercitrin may alleviate soleus muscle atrophy and mitophagy and reverse the slow-to-fast fiber type conversion following denervation via inhibition of oxidative stress and inflammatory response. Our study findings enrich the knowledge regarding the molecular regulatory mechanisms of denervated muscle atrophy and provide a scientific basis for isoquercitrin as a protective drug for the prevention and treatment of denervated muscle atrophy.

Dataset Information

Ficus carica L. Attenuates Denervated Skeletal Muscle Atrophy via PPAR?/NF-?B Pathway.

Publications

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

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