Salidroside Attenuates Denervation-Induced Skeletal Muscle Atrophy Through Negative Regulation of Pro-inflammatory Cytokine

Abstract

Skeletal muscle atrophy is associated with pro-inflammatory cytokines. Salidroside is a biologically active ingredient of Rhodiola rosea, which exhibits anti-inflammatory property. However, there is little known about the effect of salidroside on denervation-induced muscle atrophy. Therefore, the present study aimed to determine whether salidroside could protect against denervation-induced muscle atrophy and to clarify potential molecular mechanisms. Denervation caused progressive accumulation of inflammatory factors in skeletal muscle, especially interleukin 6 (IL6) and its receptor, and recombinant murine IL6 (rmIL6) local infusion could induce target muscle atrophy, suggesting that denervation induced inflammation in target muscles and the inflammation may trigger muscle wasting. Salidroside alleviated denervation-induced muscle atrophy and inhibited the production of IL6. Furthermore, the inhibition of phosphorylation of signal transducer and activator of transcription 3 (STAT3), and the decreased levels of suppressor of cytokine signaling (SOCS3), muscle RING finger protein-1 (MuRF1), atrophy F-box (atrogin-1), microtubule-associated protein light chain 3 beta (LC3B) and PTEN-induced putative kinase (PINK1) were observed in denervated muscles that were treated with salidroside. Finally, all of these responses to salidroside were replicated in neutralizing antibody against IL6. Taken together, these results suggest that salidroside alleviates denervation-induced inflammation response, thereby inhibits muscle proteolysis and muscle atrophy. Therefore, it was assumed that salidroside might be a potential therapeutic candidate to prevent muscle wasting.

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

“…Because systematic research on denervated muscle atrophy has not yet been conducted, no breakthrough has been achieved. Numerous molecules involved in denervated muscle atrophy are also involved in several events or pathways that are interconnected, including proteolytic pathways (such as the ubiquitin-proteasome pathway and autophagy-lysosomal pathway), protein synthesis pathways, and muscle fiber regeneration pathways ( Winbanks et al, 2016 ; Arouche-Delaperche et al, 2017 ; Li et al, 2017 ; Quattrocelli et al, 2017 ; Brzeszczyńska et al, 2018 ; Yin et al, 2018 ; Huang et al, 2019 ; Qiu et al, 2019 ; Wu et al, 2019 ). Moreover, interconnections between these pathways complicate the molecular mechanism of denervated muscle atrophy.…”

Effect of Chronic Intermittent Hypoxia (CIH) on Neuromuscular Junctions and Mitochondria in Slow- and Fast-Twitch Skeletal Muscle of Mice – Role of iNOS

“…As another striking similarity, we found a > 10-fold increase in SOCS3 expression with CIH vs. NOX in WT as well as with iNOS −/− vs. WT at NOX in (pooled samples of) soleus muscle. Available evidence quali es SOCS3 as a candidate to mechanistically link mitochondrial damage to NMJ deterioration: SOCS3 upregulation has been demonstrated as an early event after skeletal muscle denervation by sciatic nerve transection [37]. This obviously occurs in response to local in ammatory signals, especially via IL6 which by itself, i.e.…”

“…Peripheral nerve injury may dramatically upregulate the low constitutive iNOS expression in Schwann cells, and iNOS deletion may result in smaller regenerating myelinated bers and delayed reinnervation of muscle NMJ distal to the injury [57]. In fact, peripheral nerve dysfunction in patients suffering from OSA appears to be an early event [58], and denervation may precede muscular dysfunction, as suggested for human upper airway muscles [37,59,60] and supported by increased sarcolemmal N-CAM staining [15]. To date, no corresponding neuromuscular data exist for human locomotor muscle with OSA.…”

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

“…Increased production of reactive oxygen species (ROS) in atrophic muscle can lead to oxidative stress along with mitochondrial dysfunction and cellular damage ( Muller et al, 2007 ; Pollock et al, 2017 ; Scalabrin et al, 2019 ), and can activate or inactivate transcription factors, metabolic enzymes, and membrane channels ( Winterbourn and Hampton, 2008 ). Inflammation also contributes to the physiologic adaptation of skeletal muscle to denervation ( Ma et al, 2018 ; Shen et al, 2019 ; Wu et al, 2019 ). Atrophic muscles have elevated levels of proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1, and IL-6 ( Cea et al, 2013 ; Ma et al, 2019 ; Wu et al, 2019 ).…”

“…Inflammation also contributes to the physiologic adaptation of skeletal muscle to denervation ( Ma et al, 2018 ; Shen et al, 2019 ; Wu et al, 2019 ). Atrophic muscles have elevated levels of proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1, and IL-6 ( Cea et al, 2013 ; Ma et al, 2019 ; Wu et al, 2019 ). Local infusion of recombinant murine IL-6 was shown to induce muscle atrophy in rats ( Wu et al, 2019 ), and inhibition of IL-6 signaling alleviated the severity of muscle atrophy ( Cánoves et al, 2013 ).…”