Aspirin alleviates denervation-induced muscle atrophy via regulating the Sirt1/PGC-1α axis and STAT3 signaling

Abstract

Background: Our prior studies have shown that inflammation may play an important triggering role during the process of denervated muscle atrophy. The nonsteroidal anti-inflammatory drug aspirin exhibits the effect of anti-inflammatory factors. This study will investigate the protective effect of aspirin on denervated muscle atrophy and the underlying mechanism.Methods: Mouse models of denervated muscle atrophy were established. The protective effect of aspirin (20 mg/kg/d, i.p.) on denervated muscle atrophy was analyzed using the wet weight ratio of tibialis anterior (TA) muscle and muscle fiber cross-sectional area (CSA). The levels of inflammatory factors were detected using quantitative reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. Sirtuins1 (SIRT1)/Peroxisome Proliferator-Activated Receptor γ Co-Activator 1α (PGC-1α) and Signal transducer and activator of transcription 3 (STAT3) signaling pathway and the muscle fiber type related proteins in TA muscle after denervation were analyzed by western blot assay.Results: Intraperitoneal injection of aspirin (20 mg/kg/d) effectively alleviated denervation-induced muscle atrophy. This mainly manifested as follows: The wet weight ratio of TA muscle and muscle fiber CSA of mice treated with aspirin were significantly greater compared with mice treated with normal saline. The level of myosin heavy chain (MHC) increased, and the levels of muscle specific E3 ubiquitin ligase Muscle-specific RING finger-1 (MuRF-1) and muscle atrophy F-box (MAFbx) were decreased. Mitochondrial vacuolation and autophagy were inhibited, as evidenced by reduced level of autophagy related proteins PINK1, BNIP3, LC3B and Atg7 in mice treated with aspirin compared with mice treated with saline. In addition, aspirin treatment inhibited the slow-to-fast twitch muscle fiber conversion, which were related with triggering the expression of Sirt1 and PGC-1α. Moreover, aspirin reduced the levels of inflammatory factors interleukin-6, interleukin-1β and tumor necrosis factor-α and decreased the activation of STAT3 signaling pathway.Conclusions: This is the first study to find that aspirin can alleviate denervation-induced muscle atrophy and inhibit the type I-to-type II muscle fiber conversion and mitophagy possibly through regulating the STAT3 inflammatory signaling pathway and Sirt1/PGC-1α signal axis. This study expands our knowledge

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

“…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.…”

“…Low nutrients, disuse, systemic inflammation, unloading, chronic kidney disease (CKD), cancer, or ageing provoke a catabolic state characterized by enhanced muscle proteolysis (25,26). Our previous study also found that the expression of Atrogin-1 and MuRF-1 was significantly increased in denervated skeletal muscle, which played an important role in the degradation of muscle protein (11,14,18). The sequencing results of this study found that ubiquitin-conjugating enzyme E2O (UBE2O), WW domain containing E3 ubiquitin protein ligase 2 (WWP2), thyroid hormone receptor interactor 12 (TRIP12), HECT and RLD domain containing E3 ubiquitin protein ligase 3/4 (HERC3/4), ubiquitin-conjugating enzyme 7-interacting protein 5 (UIP5), MDM2 protooncogene (Mdm2), midline 1 (MID1), and tripartite motifcontaining 37 (Trim37) were up-regulated in denervated skeletal muscles, which confirmed the important role of ubiquitin-mediated proteolysis in the process of denervationinduced muscle atrophy.…”

“…Previous studies have examined many differentially expressed genes (DEGs) in atrophying muscles by using complementary DNA (cDNA) microarray (5,(7)(8)(9)(10). Several molecular mediators in skeletal muscles have been identified to play crucial roles in denervation-induced muscle atrophy (11)(12)(13)(14)(15)(16)(17)(18). However, it is still unclear which biological processes are affected in the process of denervation-induced muscle atrophy.…”

Manifestations of Age on Autophagy, Mitophagy and Lysosomes in Skeletal Muscle

“…Aging is associated with both neuromuscular denervation and reduced physical activity. Since it is known that denervation [ 124 , 126 , 131 , 207 , 208 , 209 , 210 , 211 , 212 , 213 ] and muscle disuse [ 214 , 215 , 216 ] independently impact mitophagic pathways, work is required to determine the independent nature of these stimuli on mitophagy. Furthermore, acute endurance exercise acts as a stimulus that promotes mitophagy in young muscle, used to prune the mitochondrial pool and create a healthier tissue [ 13 ].…”

Global alternative splicing landscape of skeletal muscle atrophy induced by hindlimb unloading

“…The cause of the atrophic phenotype is the imbalance of protein metabolism, that is, protein synthesis is inhibited and protein degradation is activated (8). Three major protein degradation pathways are activated during muscle atrophy as follows: the ubiquitin-proteasome pathway, autophagylysosome pathway, and calpain pathway (9)(10)(11). Two studies using proteomics in denervated muscle atrophy model found that a large number of protein expression changes were accompanied by muscle atrophy, ubiquitin proteasome pathway was widely activated (12)(13)(14).…”