131 - H19X-encoded Non-coding RNAs Are Associated with Loss of Muscle and Old Age in Human: A Quantitative Histological Study Using the Genotype-Tissue Expression (GTEx) Database

Poster Board Number: 131
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Abstract Body : Background and Hypothesis: Loss of skeletal muscle mass and function is commonly seen in individuals with chronic illness, older age, and altered hormonal and/or endocrine functions. Whole-genome survey of human muscle biopsies has identified several miRNAs which are associated with chronic diseases and thus named “atromiRs”. Using murine models, we have provided compelling evidence that H19X-encoded atromiRs miR-424/miR-503 downregulate muscle mass by directly targeting protein translation initiation factors. We here hypothesized that H19X-encoded non-coding RNAs (ncRNAs) are involved in the pathogenesis of muscle atrophy/wasting in humans, and the levels of the ncRNAs are correlated with the loss of skeletal muscle mass in old age.

Methods: A total of 803 samples from the GTEx project, which contains both skeletal muscle RNA expression information and skeletal muscle biopsy images, were included in the study. The samples were further classified into eight groups based on the levels of miR-503HG (host gene of miR-424/miR-503) reported in the database. Quantification of histopathology in Hematoxylin and Eosin(HE)-stained muscle sections were manually performed in group 1 (n=89) and 8 (n=100), which had the lowest levels or highest levels of miR-424/miR-503, respectively. The degree of muscle atrophy, fibrosis and connective tissue distribution, and interfascicular and perifascicular fat accumulation were assessed with a grading scale of 0-3. The total muscle histology score was additionally calculated as a sum of all three scores. Unpaired student t-tests were used to compare histological scores, BMI, and age between the two groups. The Chi-square test was used for categorical variables (sex). All tests were two-tailed and p-values less than 0.05 were considered significant.

Results: There is no significant difference between the two groups in sex (p= 0.545). In agreement with our recent study, high levels of miR-503HG (group 8) are associated with old age (p= 0.023), and a trend of higher BMI (p= 0.072). Strikingly, high levels of miR-503HG are significantly correlated with muscle atrophy (p= 0.001) and a total muscle wasting score (p= 0.027) from histological assessment.

Conclusions: These findings suggest the increased levels of H19X-encoded ncRNAs in human skeletal muscle are associated with muscle mass loss and potential sarcopenia. The results of our study may provide insight into the underlying role of H19X-encoded ncRNAs in the pathogenesis of geriatric muscle loss. The validation of genetic causes of muscle loss/wasting is rather complex considering multiple co-morbid conditions, an independent series of well-controlled human studies is therefore warranted to verify our findings.

The research was funded by the University of Houston internal fund to enhance and advance research (to YL).