MicroRNA-542 Promotes Mitochondrial Dysfunction and SMAD Activity and Is Elevated in Intensive Care Unit-Acquired Weakness

Abstract

Rationale Loss of skeletal muscle mass and function is a common consequence of critical illness and a range of chronic diseases, but the mechanisms by which this occurs are unclear. Objectives To identify microRNAs (miRNAs) that were increased in the quadriceps of patients with muscle wasting and to determine the molecular pathways by which they contributed to muscle dysfunction. Methods miRNA-542-3p/5p (miR-542-3p/5p) were quantified in the quadriceps of patients with chronic obstructive pulmonary disease and intensive care unit-acquired weakness (ICUAW). The effect of miR-542-3p/5p was determined on mitochondrial function and transforming growth factor-β signaling in vitro and in vivo. Measurements and main results miR-542-3p/5p were elevated in patients with chronic obstructive pulmonary disease but more markedly in patients with ICUAW. In vitro, miR-542-3p suppressed the expression of the mitochondrial ribosomal protein MRPS10 and reduced 12S ribosomal RNA (rRNA) expression, suggesting mitochondrial ribosomal stress. miR-542-5p increased nuclear phospho-SMAD2/3 and suppressed expression of SMAD7, SMURF1, and PPP2CA, proteins that inhibit or reduce SMAD2/3 phosphorylation, suggesting that miR-542-5p increased transforming growth factor-β signaling. In mice, miR-542 overexpression caused muscle wasting, and reduced mitochondrial function, 12S rRNA expression, and SMAD7 expression, consistent with the effects of the miRNAs in vitro. Similarly, in patients with ICUAW, the exp…