miR‐29c improves skeletal muscle mass and function throughout myocyte proliferation and differentiation and by repressing atrophy‐related genes

Abstract

AimTo identify microRNAs (miRs) involved in the regulation of skeletal muscle mass. For that purpose, we have initially utilized an in silico analysis, resulting in the identification of miR‐29c as a positive regulator of muscle mass.MethodsmiR‐29c was electrotransferred to the tibialis anterior to address its morphometric and functional properties and to determine the level of satellite cell proliferation and differentiation. qPCR was used to investigate the effect of miR‐29c overexpression on trophicity‐related genes. C2C12 cells were used to determine the impact of miR‐29c on myogenesis and a luciferase reporter assay was used to evaluate the ability of miR‐29c to bind to the MuRF1 3′UTR.ResultsThe overexpression of miR‐29c in the tibialis anterior increased muscle mass by 40%, with a corresponding increase in fibre cross‐sectional area and force and a 30% increase in length. In addition, satellite cell proliferation and differentiation were increased. In C2C12 cells, miR‐29c oligonucleotides caused increased levels of differentiation, as evidenced by an increase in eMHC immunostaining and the myotube fusion index. Accordingly, the mRNA levels of myogenic markers were also increased. Mechanistically, the overexpression of miR‐29c inhibited the expression of the muscle atrophic factors MuRF1, Atrogin‐1 and HDAC4. For the key atrogene MuRF1, we found that miR‐29c can bind to its 3′UTR to mediate repression.ConclusionsThe results herein suggest that miR‐29c can improve skeletal muscle size and function by stimulating satellite cell proliferation and repressing atrophy‐related genes. Taken together, our results indicate that miR‐29c might be useful as a future therapeutic device in diseases involving decreased skeletal muscle mass.

A new role of miR‐29c as a potent inducer of skeletal muscle hypertrophy

“…Ectopic expression of miR‐29c in C2C12 myoblasts enhanced myotube fusion and expression of myogenic markers. In addition, they reported that miR‐29c mimic inhibited the expression of the muscle atrophy‐related factors MuRF1, Atrogin‐1 and HDAC4 and provided evidence that miR‐29c targets MuRF1 transcript by binding directly to its 3′‐untranslated region (3′UTR) . These findings highlight the important role of microRNAs (miRNAs) in regulation of muscle homeostasis and indicate miR‐29c as a possible candidate for future therapeutic application in diseases involving decreased skeletal muscle mass.…”

“…Silva and colleagues give an important contribution in this regard. Indeed, they report that miR‐29c‐overexpressing mouse muscles showed increased size and length, including a higher number of serial sarcomeres, have no sign of inflammatory infiltration and generate more force, resulting in a positive adaptive response . These in vivo findings correlate with increased expression levels of differentiation specific markers and increased size of C2C12‐derived myotubes.…”

“…Having established that miR‐29c plays a crucial role in driving myogenesis, increasing muscle mass and inhibiting muscle atrophy and fibrosis, Silva and colleagues highlight that this miRNA is an ideal candidate to use as a therapeutic tool to regulate these functions in pathological conditions . One major challenge in using synthetic miRNAs for therapeutic purpose is that they are quickly degraded by the abundant ribonuclease present in tissues and in biological fluids.…”

Roles of lncRNAs and circRNAs in regulating skeletal muscle development

“…1,2 The growth and development of skeletal muscle affect life activities, and patients with many pathological conditions show abnormal muscle development, such as immobilization after fracture, Duchenne muscular dystrophy (DMD) and Facioscapulohumeral muscular dystrophy. 1,2 The growth and development of skeletal muscle affect life activities, and patients with many pathological conditions show abnormal muscle development, such as immobilization after fracture, Duchenne muscular dystrophy (DMD) and Facioscapulohumeral muscular dystrophy.…”

“…Skeletal muscle plays a crucial role in providing movement and maintaining posture. 1,2 The growth and development of skeletal muscle affect life activities, and patients with many pathological conditions show abnormal muscle development, such as immobilization after fracture, Duchenne muscular dystrophy (DMD) and Facioscapulohumeral muscular dystrophy. [3][4][5][6][7][8] The formation of skeletal muscle is known as myogenesis and requires the fusion of myoblasts to produce multinucleated fibres.…”