Mammalian skeletal muscle comprises different fiber types, whose identity is first established during embryonic development by intrinsic myogenic control mechanisms and is later modulated by neural and hormonal factors. The relative proportion of the different fiber types varies strikingly between species, and in humans shows significant variability between individuals. Myosin heavy chain isoforms, whose complete inventory and expression pattern are now available, provide a useful marker for fiber types, both for the four major forms present in trunk and limb muscles and the minor forms present in head and neck muscles. However, muscle fiber diversity involves all functional muscle cell compartments, including membrane excitation, excitation-contraction coupling, contractile machinery, cytoskeleton scaffold, and energy supply systems. Variations within each compartment are limited by the need of matching fiber type properties between different compartments. Nerve activity is a major control mechanism of the fiber type profile, and multiple signaling pathways are implicated in activity-dependent changes of muscle fibers. The characterization of these pathways is raising increasing interest in clinical medicine, given the potentially beneficial effects of muscle fiber type switching in the prevention and treatment of metabolic diseases.

Fiber types in mammalian skeletal muscles.

A Family of microRNAs Encoded by Myosin Genes Governs Myosin Expression and Muscle Performance

Skeletal muscle is the dominant organ system in locomotion and energy metabolism. Postnatal muscle grows and adapts largely by remodelling pre-existing fibres, whereas embryonic muscle grows by the proliferation of myogenic cells. Recently, the genetic hierarchies of the myogenic transcription factors that control vertebrate muscle development - by myoblast proliferation, migration, fusion and functional adaptation into fast-twitch and slow-twitch fibres - have become clearer. The transcriptional mechanisms controlling postnatal hypertrophic growth, remodelling and functional differentiation redeploy myogenic factors in concert with serum response factor (SRF), JUNB and forkhead box protein O3A (FOXO3A). It has also emerged that there is extensive post-transcriptional regulation by microRNAs in development and postnatal remodelling.

Transcriptional mechanisms regulating skeletal muscle differentiation, growth and homeostasis

MicroRNA-206: the skeletal muscle-specific myomiR

Muscle and its connective tissue are intimately linked in the embryo and in the adult, suggesting that interactions between these tissues are crucial for their development. However, the study of muscle connective tissue has been hindered by the lack of molecular markers and genetic reagents to label connective tissue fibroblasts. Here, we show that the transcription factor Tcf4 (transcription factor 7-like 2; Tcf7l2) is strongly expressed in connective tissue fibroblasts and that Tcf4GFPCre mice allow genetic manipulation of these fibroblasts. Using this new reagent, we find that connective tissue fibroblasts critically regulate two aspects of myogenesis: muscle fiber type development and maturation. Fibroblasts promote (via Tcf4-dependent signals) slow myogenesis by stimulating the expression of slow myosin heavy chain. Also, fibroblasts promote the switch from fetal to adult muscle by repressing (via Tcf4-dependent signals) the expression of developmental embryonic myosin and promoting (via a Tcf4-independent mechanism) the formation of large multinucleate myofibers. In addition, our analysis of Tcf4 function unexpectedly reveals a novel mechanism of intrinsic regulation of muscle fiber type development. Unlike other intrinsic regulators of fiber type, low levels of Tcf4 in myogenic cells promote both slow and fast myogenesis, thereby promoting overall maturation of muscle fiber type. Thus, we have identified novel extrinsic and intrinsic mechanisms regulating myogenesis. Most significantly, our data demonstrate for the first time that connective tissue is important not only for adult muscle structure and function, but is a vital component of the niche within which muscle progenitors reside and is a critical regulator of myogenesis.

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Connective tissue fibroblasts and Tcf4 regulate myogenesis

Sox6, a member of the Sox family of transcription factors, is highly expressed in skeletal muscle. Despite its abundant expression, the role of Sox6 in muscle development is not well understood. We hypothesize that, in fetal muscle, Sox6 functions as a repressor of slow fiber type-specific genes. In the wild-type mouse, differentiation of fast and slow fibers becomes apparent during late fetal stages (after approximately embryonic day 16). However, in the Sox6 null-p(100H) mutant mouse, all fetal muscle fibers maintain slow fiber characteristics, as evidenced by expression of the slow myosin heavy chain MyHC-beta. Knockdown of Sox6 expression in wild-type myotubes results in a significant increase in MyHC-beta expression, supporting our hypothesis. Analysis of the MyHC-beta promoter revealed a Sox consensus sequence that likely functions as a negative cis-regulatory element. Together, our results suggest that Sox6 plays a critical role in the fiber type differentiation of fetal skeletal muscle.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/dvdy.21223

Michael Yeh

Papers

Sox6 is required for normal fiber type differentiation of fetal skeletal muscle in mice.