MiR-19b-3p is associated with a diametric response to resistance exercise in older adults and regulates skeletal muscle anabolism via PTEN inhibition.

Donato A Rivas,Townsend Benard,Adelino Sanchez Ramos Da Silva,Roger A Fielding,Lee M Margolis,Fei Peng

doi:10.1152/ajpcell.00190.2021

Abstract

Understanding paradoxical responses to anabolic stimulation and identifying the mechanisms for this inconsistency in mobility-limited older adults may provide new targets for the treatment of sarcopenia. Our laboratory has discovered that dysregulation in microRNA (miRNA) that target anabolic pathways is a potential mechanism resulting in age-associated decreases in skeletal muscle mass and function (sarcopenia). The objective of the current study was to assess circulating miRNA expression profiles in diametric response of leg lean mass in mobility-limited older individuals after a 6-mo progressive resistance exercise training intervention (PRET) and determine the influence of differentially expressing miRNA on regulation of skeletal muscle mass. Participants were dichotomized by gain (Gainers; mean +561.4 g, n = 33) or loss (Losers; mean −589.8 g, n = 40) of leg lean mass after PRET. Gainers significantly increased fat-free mass 2.4% vs. −0.4% for Losers. Six miRNA (miR-1-3p, miR-19b-3p, miR-92a, miR-126, miR-133a-3p, and miR-133b) were significantly identified to be differentially expressed between Gainers and Losers, with miR-19b-3p being the miRNA most highly associated with increases in fat-free mass. Using an aging mouse model, we then assessed if miR-19b-3p expression was different in young mice with larger muscle mass compared with older mice. Circulating and skeletal muscle miR-19b-3p expression was higher in young compared with old mice and was positively associated with muscle mass and grip strength. We then used a novel integrative approach to determine if differences in circulating miR-19b-3p potentially translate to augmented anabolic response in human skeletal muscle cells in vitro. Results from this analysis identified that overexpression of miR-19b-3p targeted and downregulated PTEN by 64% to facilitate significant ∼50% increase in muscle protein synthetic rate as measured with SUnSET. The combine results of these three models identify miR-19b-3p as a potent regulator of muscle anabolism that may contribute to an inter-individual response to PRET in mobility-limited older adults.

Highlights

Age-associated decreases in skeletal muscle mass and function limit older individuals’ mobility and independence and are risk factors for mortality [1]
We found a diametric response of leg lean mass in mobility-limited older individuals after a 6-mo progressive resistance exercise training intervention (PRET)
All participants were weight stable, normal to slightly obese, not participating in structured exercise 6 mo before starting the study, and were functionally limited [short physical performance battery (SPPB) score 10]

Summary

Introduction

Age-associated decreases in skeletal muscle mass and function (sarcopenia) limit older individuals’ mobility and independence and are risk factors for mortality [1]. Increasing muscle size requires a chronic net positive protein balance, favoring muscle protein synthesis over protein breakdown [5]. Molecular processes regulating muscle protein turnover are complex cellular pathways that include alterations to signaling proteins, gene transcription, and microRNA (miRNA) expression [7, 8]. There is abundant evidence showing that exercise and nutrition are powerful independent stimulators of skeletal muscle protein synthesis with the ability to shift net protein balance from negative to positive [9,10,11]. A combination of resistance exercise training and nutrients could augment the individual effects of both these stimuli on anabolic signaling, transcriptional pathways, and posttranscriptional regulators

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