The Molecular Regulatory Mechanisms Of Human Skeletal Muscle Atrophy Induced By Short Duration Altitude Exposure

Obejective: Inducing human skeletal muscle atrophy by short duration natural altitude exposure.Profiling the whole genome m RNA expression of the skeleton muscle before and after the exposure.Identify the molecular regulation mechanisms,which play key roles during the process of altitude/hypoxia induced muscle atropy,by bioinformatics approaches.Provide the supportive data for the future research of regulation mechanisms during muscle atrophy.Methods: 10 male healthy sea level dwellers were recruited for the study.The subjects traveled to Lhasa(3700m),Tibet and lived for 11 days.During the altitude exposure,the subjects were instructed to maintain their normal daily activity the same as the sea level.The subjects were provided the same dishes during each meal and eat together without any restrictions on food selection and quantity.Body composition,cross sectional area of thigh muscle and biopsy sampling on vastus lateralis were carried out before and after the altitude exposure.Muscle transcriptome profiling was performed by a whole genome transcriptome array.RT-PCR were performed to verify the results from the array tests.Perform the GO annotation,pathway enrichment analysis,transcriptional factor prediction and kinase enrichment analysis by bioinformatics approaches.Results: The body weight(73.2±9.7kg vs.71.0±9.2kg,P<0.01),whole body muscle mass(58.1±7.1kg vs.57.1±7.1kg,P<0.01)and whole body fat mass(12.0±4.4kg vs.11.2±4.0kg,P<0.05)decreased significantly after vs.before the altitude exposure.904 genes were differentially expressed after the altitude exposure,among which578 genes were up regulated and 326 genes were down regulated.The pathways of ubiquitin meditated proteolysis,regulation of actin cytoskeleton and PI3K-AKT were modulated towards the catabolic effects of muscle protein.The expression of genes encoding key muscle atrophy proteins such as Mu RF1,MAFbx,Myostatin,GSK3? and FOXO,etc.were significantly changed.Transcription factor prediction showed that SMAD2,SMAD3,E2F4 and CUX1 might be the key regulator in the signaling of altitude induced muscle atrophy.Conclusion: Exposure to natural altitude of 3700 m for 11 days induced significant muscle atrophy.The pathway changes of ubiquitin meditated proteolysis,regulation of actin cytoskeleton and PI3K-AKT and expression changes of Mu RF1,MAFbx,Myostatin,GSK3? and FOXO genes might be the possible mechanisms for altitude induced skeletal mucle atrophy.