MicroRNAs in muscle wasting

Skeletal muscle makes up approximately 40% of the total body mass; it is essential in providing structural support, to regulate motion and as an energy store, thereby playing a major role in the overall metabolism. Skeletal muscle retains a high plasticity in order to respond to various stimuli, which subsequently lead to changes in gene transcription and translation. Aside from the obvious transcription factors, non‐coding RNAs have received much attention over the last decade and can be subclassed into long non‐coding RNA and small non‐coding RNA termed microRNA (miR). These miRs are similar to mRNA when first transcribed as primary RNA and are subsequently processed by the endoribonuclease DROSHA associated with PASHA to a precursor miR, which is further processed by the endoribonuclease DICER1 to form mature miRs.1 The mature miR binds to its target mRNAs leading to a blocked translation or degradation thereby providing the cell with a post‐transcriptional control of gene expression.2, 3 While some miRs are expressed ubiquitously in most tissues and cell types, other miRs are highly and specifically enriched in certain tissues.4 MyomiRs comprise a group of miRs, who display an enriched expression in skeletal muscle including miR‐1, miR‐133a, miR‐133b, miR‐206, miR‐208, miR‐208b, miR‐486, and miR‐499. These miRs are under the transcriptional control of myogenic regulatory factors such as MyoD, myogenin, Myf5, and MRF4.5 The expression of MyomiRs is modulated in skeletal muscle growth, its development and maintenance, and during atrophy.5 Two key players of muscle wasting are the E3 ubiquitin ligases MAFbx and MuRF‐1, the latter being the only E3 ubiquitin ligase known to target contractile proteins in catabolic conditions6 and which can be inhibited by small molecules.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.8 In contrast to healthy adaptation, not only myomiRs are regulated in cancer cachexia, a recent publication showed an up‐regulation of hsa‐miR‐3184‐3p, hsa‐miR‐423‐5p, hsa‐let‐7d‐3p, hsa‐miR‐1296‐5p, hsa‐miR‐345‐5p, hsa‐miR‐532‐5p, hsa‐miR‐423‐3p, and hsa‐miR‐199a‐3p, but no down‐regulation of miRs in skeletal muscle biopsies of patients with pancreatic and colorectal cancer (Table 1). 9 In a rat model of paralysed muscle by spinal cord injury, a down‐regulation of miRs 23a, 23b, 27b, 145, and 206 was observed 56 days after injury,10 while injection of 30 μg of mir‐206 attenuated muscle loss in a rat denervation model.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 post‐operative week (r = −0.57, P < 0.001). 14 Overexpression of miR‐23a/27a in muscle attenuated diabetes‐induced muscle cachexia and attenuates renal fibrosis lesions via muscle‐kidney crosstalk in streptozotocin‐induced diabetic mice.15 Recently, the lncRNA MAR1 has been shown to act as a miR‐487b scavenger to regulate Wnt5a protein expression leading to stimulated muscle differentiation and regeneration as well as increased strength in mice16 making the already complex miR regulatory system even more complicated. Table 1 Differential regulation of miR expression in skeletal muscle after exercise