Isoquercitrin Delays Denervated Soleus Muscle Atrophy by Inhibiting Oxidative Stress and Inflammation

Abstract

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 ubiquitinproteasome 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 γ coactivator 1α (PGC-1α); 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)-1β, IL-6, and tumor necrosis factor-α (TNF-α)-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.

Transcriptome sequencing and analysis reveals the molecular mechanism of skeletal muscle atrophy induced by denervation

“…It is widely activated during muscle atrophy and leads to muscle mass loss in varying degrees (28). Our previous study also found that ALS is widely activated in the process of denervation-induced muscle atrophy (6,12,14). The results of this study also confirm our previous results.…”

“…Our study showed that ubiquitin-proteasome system and autophagy lysosomal system are activated in the process of denervationinduced muscle atrophy, but the trigger factors that initiate their activation are not yet clear. Our previous studies suggested that oxidative stress and inflammation may be the trigger factors for activation of the ubiquitin-proteasome and autophagy lysosomal systems (6,18,31). Further studies are needed to confirm the possible molecular mechanism.…”

“…The proteolytic systems mainly include ubiquitin proteasome system (UPS), autophagy lysosome system (ALS), cathepsin hydrolysis system, and so on. The activation of these proteolytic pathways in the process of skeletal muscle atrophy involves a very complex molecular mechanism (6). Following activation, the proteolytic pathways hydrolyze myofibrils and cause skeletal muscle atrophy.…”

Acute glucose fluctuation promotes in vitro intestinal epithelial cell apoptosis and inflammation via the NOX4/ROS/JAK/STAT3 signaling pathway

“…Studies have demonstrated that oxidative stress can cause inflammation, but no inflammation occurs during cell apoptosis ( 41 , 42 ). Inflammation will further aggravate oxidative stress and IL-6 can play an important role through the JAK/STAT3 pathway ( 43 ). In the present study, oxidative stress was caused by glucose fluctuation.…”

Master Regulators of Muscle Atrophy: Role of Costamere Components

“…Inflammation contributes to muscle atrophy development in several contexts [ 241 ]. Its early activation after denervation might be related to nerve injury and stump degeneration [ 242 ] and/or to the early increase in muscle levels of oxidative stress, as suggested by the upregulation of cytochrome P450 and monooxygenase transcripts, together with others involved in the anti-oxidant defense, about 3 h after denervation [ 87 , 243 ]. Activation of NF-κB and pro-inflammatory cytokines, secondary to de novo expression of connexins after one-week denervation, also contributes to muscle atrophy [ 213 ].…”