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

Abstract

Elevated miR-542-3p/5p may cause muscle atrophy in intensive care unit patients through the promotion of mitochondrial dysfunction and activation of SMAD2/3 phosphorylation.

Mitochondrial regulation in skeletal muscle: A role for non‐coding RNAs?

“…A series of nuclear‐encoded miRNAs located in the cytoplasm specifically modulates mitochondrial metabolism and function in skeletal muscle [reviewed by our group (Russell et al., ; Tsitkanou, Della Gatta, & Russell, ) and others (Lima et al., ; Massart, Katayama, & Krook, )]. Of particular interest are miR‐494 (Yamamoto et al., ), miR‐23a (Russell et al., 2013; Wada et al., ), miR‐696 (Aoi et al., ) and miR‐542 (Garros et al., ). These miRNAs indirectly or directly target key, nuclear‐encoded regulators of the mitochondrial function, including mitochondrial transcription factor A ( Tfam ; Yamamoto et al., ), peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha ( Pgc‐1α ; Aoi et al., ; Russell et al., 2013), cytochrome b and cytochrome c oxidase complex IV ( Cox4 ; Wada et al., ) and mitochondrial ribosomal protein MRPS10 (Garros et al., ).…”

“…Of particular interest are miR‐494 (Yamamoto et al., ), miR‐23a (Russell et al., 2013; Wada et al., ), miR‐696 (Aoi et al., ) and miR‐542 (Garros et al., ). These miRNAs indirectly or directly target key, nuclear‐encoded regulators of the mitochondrial function, including mitochondrial transcription factor A ( Tfam ; Yamamoto et al., ), peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha ( Pgc‐1α ; Aoi et al., ; Russell et al., 2013), cytochrome b and cytochrome c oxidase complex IV ( Cox4 ; Wada et al., ) and mitochondrial ribosomal protein MRPS10 (Garros et al., ). Of these miRNAs, miR‐23a and miR‐542 are also expressed in human myotube mitochondria (Barrey et al., ), although no putative canonical target site for miR‐23a or miR‐542 was found in any mitochondrial transcript (Barrey et al., ).…”

MicroRNAs in muscle wasting

“…5 The expression of MyomiRs is modulated in skeletal muscle growth, its development and maintenance, and during atrophy. 12 In patients with COPD with a low fat free mass, an increased expression of miR-675 in quadricep muscle was shown to repress muscle regeneration in vitro. 7 The related proteins MuRF-2 and MuRF-3 bind to microtubules and are implicated in sarcomere formation with evident functional redundancy, which has proven to be important for the maintenance of skeletal muscle, as double knockout mice lead to myopathy, reduced fore generation, and fibre type shift.…”

“…11 In patients with chronic obstructive pulmonary disease (COPD), an up-regulation of miR-542-3p/5p in quadricep muscle has been described, which caused muscle wasting and reduced mitochondrial function when overexpressed in mice possibly due to a suppression of the mitochondrial ribosomal protein MRPS10, reduced 12S ribosomal RNA expression, and increased TGF-b signalling. 12 In patients with COPD with a low fat free mass, an increased expression of miR-675 in quadricep muscle was shown to repress muscle regeneration in vitro. 13 Moreover, quadricep expression of miR-422a was positively associated with muscle strength (maximal voluntary contraction r = 0.59, P < 0.001 and r = 0.51, P = 0.004, for COPD and aortic surgery, respectively) and inversely associated with the amount of muscle that would be lost in the first postoperative week (r = À0.57, P < 0.001).…”

Exploring the Potential Effectiveness of Combining Optimal Nutrition With Electrical Stimulation to Maintain Muscle Health in Critical Illness: A Narrative Review

“…However it is important to recognize that the response to nutrition and exercise interventions is likely to be influenced by a number of patient characteristics, including sarcopenia, age, comorbidities, and obesity. Recent work has also proposed that genetic predisposition may predict the extent of muscle wasting . Therefore, consideration and categorization of the patient population are vital.…”