Microarray Analysis of Gene Expression Provides New Insights Into Denervation-Induced Skeletal Muscle Atrophy

Abstract

Denervation induces skeletal muscle atrophy, accompanied by complex biochemical and physiological changes, with potentially devastating outcomes even an increased mortality. Currently, however, there remains a paucity of effective strategies to treat skeletal muscle atrophy. Therefore, it is required to understand the molecular mechanisms of skeletal muscle atrophy and formulate new treatment strategies. In this study, we investigated the transcriptional profile of denervated skeletal muscle after peripheral nerve injury in rats. The cDNA microarray analysis showed that a huge number of genes in tibialis anterior (TA) muscles were differentially expressed at different times after sciatic nerve transection. Notably, the 24 h of denervation might be a critical time point for triggering TA muscle atrophy. According to the data from self-organizing map (SOM), Pearson correlation heatmap, principal component analysis (PCA), and hierarchical clustering analysis, three nodal transitions in gene expression profile of the denervated TA muscle might partition the period of 0.25 h–28 days post nerve injury into four distinct transcriptional phases. Moreover, the four transcriptional phases were designated as “oxidative stress stage”, “inflammation stage”, “atrophy stage” and “atrophic fibrosis stage”, respectively, which was concluded from Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene ontology (GO) analyses at each transcriptional phase. Importantly, the differentially expressed genes at 24 h post sciatic nerve transection seemed to be mainly involved in inflammation, which might be a critical process in denervation-induced muscle atrophy. Overall, our study would contribute to the understanding of molecular aspects of denervation-induced muscle atrophy, and may also provide a new insight into the time window for targeted therapy.

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

“…Recently, we used transcriptome sequencing and bioinformatics methods to systematically analyze the differentially expressed genes involved in denervated muscle atrophy. To the best of our knowledge, it was proposed for the first time that denervated muscle atrophy can be divided into four different transcription stages (Shen et al, 2019). In the oxidative stress stage (0-12 h), oxidative stress occurs early after skeletal muscle denervation, which may be attributed to the loss of contractile function of the target muscle, resulting in decreased blood perfusion in the muscle.…”

“…These inflammatory factors cause further inflammation by activating inflammatory response pathways. In the atrophic (3-7 days) and atrophic fibrosis (14-28 days) stages, excessively activated inflammation further initiates the downstream muscle atrophic process, thereby promoting target muscle atrophy and fibrosis (Shen et al, 2019). Overall, oxidative stress, inflammation, atrophy, and atrophic fibrosis sequentially occur following skeletal muscle denervation.…”

Time course analysis of large-scale gene expression in incised muscle using correspondence analysis

“…results [16][17][18][19][20]. In many cases, researchers select genes that are upregulated or downregulated more than a specific threshold in a microarray analysis, then perform GO and pathway analysis [20][21][22][23][24][25][26]. However, Yang et al [27] suggested that genes fluctuating less at a significant level could also be of importance for the understanding of specific reactions.…”

“…However, Yang et al [27] suggested that genes fluctuating less at a significant level could also be of importance for the understanding of specific reactions. Shen et al [20]…”

Effects of Resistance Training and Bowdichia virgilioides Hydroethanolic Extract on Oxidative Stress Markers in Rats Submitted to Peripheral Nerve Injury

“…Damage to nerve endings promoted by PNI leads to the disuse of the skeletal muscle innervated by the injured branch [ 15 ]. Therefore, ischemic and inflammatory processes are involved, resulting in the emergence of oxidative stress (OS) [ 15 , 16 ]. Once the peripheral nerve suffers damage, there is accumulation of pro-oxidant substances; simultaneously, the levels of endogenous antioxidants are insufficient to maintain resistance to oxidative damage [ 15 ].…”