miR‐206 family is important for mitochondrial and muscle function, but not essential for myogenesis in vitro

Abstract

miR‐206, miR‐1a‐1, and miR‐1a‐2 are induced during differentiation of skeletal myoblasts and promote myogenesis in vitro. miR‐206 is required for skeletal muscle regeneration in vivo. Although this miRNA family is hypothesized to play an essential role in differentiation, a triple knock‐out (tKO) of the three genes has not been done to test this hypothesis. We report that tKO C2C12 myoblasts generated using CRISPR/Cas9 method differentiate despite the expected derepression of the miRNA targets. Surprisingly, their mitochondrial function is diminished. tKO mice demonstrate partial embryonic lethality, most likely due to the role of miR‐1a in cardiac muscle differentiation. Two tKO mice survive and grow normally to adulthood with smaller myofiber diameter, diminished physical performance, and an increase in PAX7 positive satellite cells. Thus, unlike other miRNAs important in other differentiation pathways, the miR‐206 family is not absolutely essential for myogenesis and is instead a modulator of optimal differentiation of skeletal myoblasts.

miR-206 enforces a slow muscle phenotype

“…However, a recent gene expression analysis of single SOL myofibers revealed that fast oxidative fibers (types IIa and IIx) are characterized by a stronger mitochondrial and electron transport chain signature than Type I, which is consistent with our overall change in gene expression and fiber type profiles (Chemello et al, 2019). In recently published work, a mouse in which miR-206 and both miR-1a loci were knocked out resulted in partial embryonic lethality, but miR-206 single KO mice and two surviving triple KO (tKO) individuals exhibited decreased physical performance, which was supported by impaired mitochondrial function in a tKO cell culture model (Przanowska et al, 2020). Although slow skeletal muscles were not examined in that study, it would be interesting to perform a metabolic analysis of slow oxidative muscles in single, double and triple miR-1/206 family KO mice.…”

miR-1 sustains muscle physiology by controlling V-ATPase complex assembly

“…S2, B and C). However, similar to mouse skeletal muscle, where loss of miR-1 causes disruption of mitochondrial structure and function ( 11 , 23 ), we found that miR-1–deficient L1 larvae displayed significant fragmentation of the otherwise extensive tubular mitochondrial network in the body-wall muscle ( Fig. 1A and fig.…”

Non-Coding RNAs as Regulators of Myogenesis and Postexercise Muscle Regeneration

“…However, the authors confirmed that miR-206 promotes myogenic cell differentiation by suppressing factors preventing its progression, i.e., PAX7 as well as NOTCH3 and IGFBP5 [57]. This stays in line with the report by Przanowska et al, 2020, who revealed that triple knockout mice devoid of miR206/miR1a1/miR1a2 are characterized by a higher number of PAX7 positive cells [58]. Apart from MyomiRs, also other non-muscle-specific miRNAs are involved in the formation and functioning of skeletal muscles.…”