The miR-206/133b cluster is dispensable for development, survival and regeneration of skeletal muscle

Abstract

BackgroundThree different gene clusters code for the muscle-specific miRNAs miR-206, miR-1 and miR-133a/b. The two miR-1/133a clusters generate identical mature miR-1 and miR-133a miRNAs in heart and skeletal muscle, while the cognate miR-206/133b cluster is exclusively expressed in skeletal muscle. Since sequences of the miRNAs miR-133a and miR-133b are almost identical, it seems likely that they share potential targets. Similarly, miR-1 and miR-206 are structurally related and contain identical seed sequences important for miRNA-target recognition. In the past, different functions of these miRNAs were suggested for development, function and regeneration of skeletal muscle using different in vivo and in vitro models; however, mutants lacking the complete miR-206/133b cluster, which generates a single pri-miRNA constituting a functional unit, have not been analyzed.MethodsWe generated miR-206/133b knock-out mice and analyzed these mice morphologically; at the transcriptome and proteome level to elucidate the contribution of this miRNA cluster for skeletal muscle development, differentiation, regeneration in vivo; and by systematic analysis. In addition, we studied the consequences of a genetic loss of miR-206/133b for expression of Pax7 and satellite cell differentiation in vitro.ResultsDeletion of the miR-206/133b cluster did not reveal any obvious essential function of the miRNA-cluster for development and differentiation of skeletal muscle. Careful examination of skeletal muscles of miR-206/133b mutants revealed no structural alterations or molecular changes at the transcriptome and proteome level. In contrast to previous studies, deletion of the miR-206/133b cluster did not impair regeneration of skeletal muscle in mdx mice. Likewise, differentiation of miR-206/133b deficient satellite cells in vitro was unaffected and no change in Pax7 protein concentration was apparent.ConclusionsWe conclude that the miR-206/133b cluster is dispensable for development, function and regeneration of skeletal muscle, probably due to overlapping functions of the related miR-1/133a clusters, which are strongly expressed in skeletal muscle. We reason that the miR-206/133b cluster alone is not an essential regulator of skeletal muscle regeneration, although more subtle functions might exist that are not apparent under laboratory conditions.

Myogenic Progenitor Cells Control Extracellular Matrix Production by Fibroblasts during Skeletal Muscle Hypertrophy

“…miR-206 is known to be involved in the regulation of satellite cell behavior and muscle regeneration (Chen et al, 2010; Liu et al, 2012), with the loss of miR-206 negatively affecting regeneration (Liu et al, 2012). However, evidence also exists that miR-206 is dispensable for muscle regeneration (Boettger et al, 2014). In the current study, we observed an expansion of Tcf4+ cells with overload that was unaffected by satellite cell depletion, suggesting that ECM synthesis increased on a per-cell basis in the absence of MPC-derived miR-206.…”

Clustered miRNAs and their role in biological functions and diseases

“…Similarly, regulation by miR‐17/92 is reported during cardiomyocyte proliferation (Yan & Jiao, ). miR‐23/24 clusters play a critical role in T‐cell differentiation (Kroesen et al, ) and miR‐206/133b cluster is important for skeletal muscle development, regeneration and differentiation (Boettger et al, ). Members of miR‐17/92 and miR‐106a/363 clusters contribute to pre‐eclampsia and reduce trophoblast differentiation by inhibiting human glial cells missing homolog 1 (hGCM1) and human cytochrome P450 family 19 subfamily A member 1 (hCYP19A1) (Kumar et al, ).…”

miR-378a-3p promotes differentiation and inhibits proliferation of myoblasts by targeting HDAC4 in skeletal muscle development

“…These miRNAs also play roles in muscle development in mammals. Previous studies reported that several miRNAs, such as miR-1, 47 miR-133, 31,45,49 and miR-206, 3,19,42 are musclespecific miRNAs because they are key regulators in muscle development in human, pigs, and rats. Others miRNAs may also contribute to muscle development.…”