The Inhibition of Autophagy and Pyroptosis by an Ethanol Extract of Nelumbo nucifera Leaf Contributes to the Amelioration of Dexamethasone-Induced Muscle Atrophy

Abstract

Muscle atrophy is characterized by a decline in muscle mass and function. Excessive glucocorticoids in the body due to aging or drug treatment can promote muscle wasting. In this study, we investigated the preventive effect of Nelumbo nucifera leaf (NNL) ethanolic extract on muscle atrophy induced by dexamethasone (DEX), a synthetic glucocorticoid, in mice and its underlying mechanisms. The administration of NNL extract increased weight, cross-sectional area, and grip strength of quadriceps (QD) and gastrocnemius (GA) muscles in DEX-induced muscle atrophy in mice. The NNL extract administration decreased the expression of muscle atrophic factors, such as muscle RING-finger protein-1 and atrogin-1, and autophagy factors, such as Beclin-1, microtubule-associated protein 1A/1B-light chain 3 (LC3-I/II), and sequestosome 1 (p62/SQSTM1) in DEX-injected mice. DEX injection increased the protein expression levels of NOD-like receptor pyrin domain-containing protein 3 (NLRP3), cleaved-caspase-1, interleukin-1beta (IL-1β), and cleaved-gasdermin D (GSDMD), which were significantly reduced by NNL extract administration (500 mg/kg/day). In vitro studies using C2C12 myotubes also revealed that NNL extract treatment inhibited the DEX-induced increase in autophagy factors, pyroptosis-related factors, and NF-κB. Overall, the NNL extract prevented DEX-induced muscle atrophy by downregulating the ubiquitin–proteasome system, autophagy pathway, and GSDMD-mediated pyroptosis pathway, which are involved in muscle degradation.

Aerobic Exercise Ameliorates Muscle Atrophy Induced by Methylglyoxal via Increasing Gastrocnemius and Extensor Digitorum Longus Muscle Sensitivity

“…1 , 4 , 6 ). Based on our data, we suggest that MGO may be one of major risk factor as an endogenous molecule in human body on the induction of skeletal muscle atrophy as similar as dexamethasone, which causes muscle atrophy as an exogenous compound ( Park et al ., 2023 ). Also, MGO, as an endogenous toxic molecule, may be a key target for regulating the skeletal muscle atrophy.…”

“…GCM is the main muscle that maintains the balance in muscle metabolism ( Yang et al ., 2022 ). A few studies have revealed that GCM muscles are contributed in the regulation of muscle metabolism in muscle atrophy models ( Honda et al ., 2022 ; Jhuo et al ., 2023 ; Park et al ., 2023 ). In this work, it found that aerobic exercise strongly restored decreased GCM muscle mass and increased the levels of atrophic factors ( i.e.…”

“…In this work, it found that aerobic exercise strongly restored decreased GCM muscle mass and increased the levels of atrophic factors (i.e., MuRF1 and MAFbx/atrogin-1) in mice with MGO-induced muscle atrophy, probably due to the regulation of protein degradation. The ubiquitin ligases MuRF1 and MAFbx/atrogin-1 are related to muscle atrophy induced by drug inducers such as dexamethasone, which contribute to muscle dysfunction (Park et al, 2023). Moreover, the upregulation of PI3K/AKT signaling in skeletal muscle is related to protein synthesis, improving the inhibition of the ubiquitin ligase-dependent proteolytic pathway (Shi et al, 2023).…”

“…The grip strength of each mouse was analyzed as maximal muscle strength ( Park et al ., 2023 ). The mice grasped a piece of green steel connected to a force gauge.…”

The roles of ubiquitination and deubiquitination of NLRP3 inflammasome in inflammation-related diseases: A review

“…This suggests that the extract may degrade NLRP3 inflammasomes by blocking both the Beclin-1/LC3I/II-mediated autophagy pathway and the Murf1/Atrogin-1-mediated UPS pathways. Consequently, the extract appears to inhibit inflammatory responses and pyroptosis in C2C12 myofibroblasts, thereby alleviating muscle atrophy [ 87 ]. In conclusion, the enhancement of autophagy appears to synergize with ubiquitination modifications to degrade NLRP3 inflammasomes effectively, thereby ameliorating inflammatory injury ( Figure 2 ).…”