Abstract
Denervated muscle atrophy is a common clinical disease that has no effective treatments. Our previous studies have found that oxidative stress and inflammation play an important role in the process of denervated muscle atrophy. Extracellular vesicles derived from skin precursor-derived Schwann cells (SKP-SC-EVs) contain a large amount of antioxidants and anti-inflammatory factors. This study explored whether SKP-SC-EVs alleviate denervated muscle atrophy by inhibiting oxidative stress and inflammation. In vitro studies have found that SKP-SC-EVs can be internalized and caught by myoblasts to promote the proliferation and differentiation of myoblasts. Nutrient deprivation can cause myotube atrophy, accompanied by oxidative stress and inflammation. However, SKP-SC-EVs can inhibit oxidative stress and inflammation caused by nutritional deprivation and subsequently relieve myotube atrophy. Moreover, there is a remarkable dose-effect relationship. In vivo studies have found that SKP-SC-EVs can significantly inhibit a denervation-induced decrease in the wet weight ratio and myofiber cross-sectional area of target muscles. Furthermore, SKP-SC-EVs can dramatically inhibit highly expressed Muscle RING Finger 1 and Muscle Atrophy F-box in target muscles under denervation and reduce the degradation of the myotube heavy chain. SKP-SC-EVs may reduce mitochondrial vacuolar degeneration and autophagy in denervated muscles by inhibiting autophagy-related proteins (i.e., PINK1, BNIP3, LC3B, and ATG7). Moreover, SKP-SC-EVs may improve microvessels and blood perfusion in denervated skeletal muscles by enhancing the proliferation of vascular endothelial cells. SKP-SC-EVs can also significantly inhibit the production of reactive oxygen species (ROS) in target muscles after denervation, which indicates that SKP-SC-EVs elicit their role by upregulating Nrf2 and downregulating ROS production-related factors (Nox2 and Nox4). In addition, SKP-SC-EVs can significantly reduce the levels of interleukin 1β, interleukin-6, and tumor necrosis factor α in target muscles. To conclude, SKP-SC-EVs may alleviate the decrease of target muscle blood perfusion and passivate the activities of ubiquitin-proteasome and autophagy-lysosome systems by inhibiting oxidative stress and inflammatory response, then reduce skeletal muscle atrophy caused by denervation. This study not only enriches the molecular regulation mechanism of denervated muscle atrophy, but also provides a scientific basis for SKP-SC-EVs as a protective drug to prevent and treat muscle atrophy.
Highlights
Skeletal muscle is an important effector organ of the peripheral nervous system, and the structural integrity and functional maintenance are both innervated and controlled by the nervous system [1]
This study explored the effects of Skin-derived precursors pre-differentiated into Schwann cells (SKP-SCs)-Extracellular vesicles (EVs) on denervated muscle atrophy, analyzed the inhibitory effects of SKP-SC-EVs on oxidative stress and inflammation caused by denervation, investigated the effect of SKP-SC-EVs on target muscle ischemia caused by denervation, and clarified the influence of SKP-SC-EVs on the ubiquitinproteasome system (UPS) and autophagy-lysosome system (ALS) pathways during the process of muscle atrophy
These results indicated that SKPThis study confirmed that inflammation is significantly activated during atrodenSC-EVs can inhibit oxidative stress responses that occur during denervated muscle ervated muscle atrophy
Summary
Skeletal muscle is an important effector organ of the peripheral nervous system, and the structural integrity and functional maintenance are both innervated and controlled by the nervous system [1]. A series of pathological changes, such as reduced muscle fiber cross-sectional area (CSA), destruction of the myofilament sarcomere, decelerated voluntary contraction, and fibrosis, eventually leads to skeletal muscle atrophy and even disability [2]. This impairs quality of life, increases morbidity and mortality, and places heavy burdens on family and society [3]. A better understanding of the mechanism by which peripheral nerve injury leads to muscle atrophy is crucial; actively seeking targets for the treatment of muscle atrophy is an important step toward solving a series of problems, such as the recovery of target muscle function after peripheral nerve injury and even the reversal of atrophy
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