Skeletal muscle specific microRNA 206 and 486 observed in circulation are biomarkers of aging

Abstract

Aging results in altered expression of microRNAs (miR) that regulate regenerative and hypertrophic processes, contributing to diminished skeletal muscle mass. Recently, miR have been shown to be present in circulation (c‐miR), and increased c‐miR are associated with disease states that negatively impact skeletal muscle. Whether c‐miR expression is altered by aging remains unknown. The objective of this investigation was to determine the influence of aging on c‐miR at rest in eighteen male volunteers (Younger (YNG) n = 9, age 22 ± 1 yrs; Older (OLD) n = 9, age 74 ± 2 yrs) and assess the relationships of c‐miR to skeletal muscle miR expression, body composition, and glucose and triglyceride concentrations. The expression of 84 c‐miR were determined in serum using a miScript miRNA PCR Array. Expression of 31 c‐miR were higher in OLD compared to YNG (> ±1.5 fold), of these 10 c‐miR achieved statistical significance (P < 0.05), with miR‐206, which is exclusive to skeletal muscle, having the greatest fold difference (3.46 ± 0.86). To assess the relationship of c‐miR to skeletal muscle miR expression, a miR Score was calculated as median fold change for 13 of the 31 c‐miR that were previously analyzed in skeletal muscle. An inverse association was observed (r = −0.45, r2 = 0.26), where miR Scores were significantly higher in serum (YNG 0.82 ± 0.16, OLD 1.42 ± 0.20; P = 0.04) and lower in skeletal muscle (YNG 1.3 ± 0.16, OLD 0.85 ± 0.08; P = 0.02) in OLD compared to YNG. Stepwise discriminant analysis revealed four c‐miR (miR‐19b‐3p, miR‐206, miR‐221‐3p, miR‐486) that correctly classified 93% of participants as YNG or OLD. Receiver operating characteristic (ROC) curve analysis on these four c‐miR determined that c‐miR 206 and 486 were able to differentiate OLD versus YNG with an area under the curve of 0.79 and 0.82, respectively. With cut off values of 1.51 and 1.53 for c‐miR 206 and 486, respectively, sensitivity was 78% and specificity was 87% for both. Backwards linear regression analysis determined triglyceride concentrations accounted for the majority of the variance (r = 0.68, r2 = 0.47; P < 0.01) for c‐miR 206 expression, while fat mass and glucose concentration accounted for the majority of the variance (r = 0.72, r2 = 0.52; P < 0.01) for c‐miR 486 expression. These findings indicate that similar to disease states which negatively impact skeletal muscle, aging results in elevation of skeletal muscle specific c‐miR. Interestingly, though c‐miR 206 and 486 were shown to be sensitive and specific to aging, differences between YNG and OLD appear to be primarily driven by fat mass, and glucose and triglyceride concentrations. Future investigations are warranted to determine if alterations in body composition, glucose and triglycerides influence the expression of c‐miR.Support or Funding InformationFunding supported by T32 NIDDK training grant # 5T32DK062032‐23, USDA agreement No. 58‐1950‐4‐003, NIA K01 award # KAG047247A‐A1, and the Boston Claude D. Pepper Center OAIC (1P30AG031679)