Skeletal muscle fiber type: using insights from muscle developmental biology to dissect targets for susceptibility and resistance to muscle disease

Abstract

Skeletal muscle fibers are classified into fiber types, in particular, slow twitch versus fast twitch. Muscle fiber types are generally defined by the particular myosin heavy chain isoforms that they express, but many other components contribute to a fiber's physiological characteristics. Skeletal muscle fiber type can have a profound impact on muscle diseases, including certain muscular dystrophies and sarcopenia, the aging-induced loss of muscle mass and strength. These findings suggest that some muscle diseases may be treated by shifting fiber type characteristics either from slow to fast, or fast to slow phenotypes, depending on the disease. Recent studies have begun to address which components of muscle fiber types mediate their susceptibility or resistance to muscle disease. However, for many diseases it remains largely unclear why certain fiber types are affected. A substantial body of work has revealed molecular pathways that regulate muscle fiber type plasticity and early developmental muscle fiber identity. For instance, recent studies have revealed many factors that regulate muscle fiber type through modulating the activity of the muscle regulatory transcription factor MYOD1. Future studies of muscle fiber type development in animal models will continue to enhance our understanding of factors and pathways that may provide therapeutic targets to treat muscle diseases. WIREs Dev Biol 2016, 5:518-534. doi: 10.1002/wdev.230 For further resources related to this article, please visit the WIREs website.

Figure 1

Skeletal muscle fiber types. (A) Section of human muscle, where fiber types have been differentiated using ATPase staining after pre-incubation at pH 4.6. (B) Illustration showing healthy muscle fibers. Connective tissue (green) interacts with the dystrophin-related complex via basal lamina. Muscle fiber nuclei (orange) are found in peripheral positions. Different fiber types, including type 1 (red), type 2A (pink), and type 2X (purple), can be intermingled within a single mammalian muscle. (C) Particular muscle groups can also be enriched for slow (Soleus) or fast (extensor digitorus longus [EDL]) muscle. In mouse, an additional fast fiber type, 2B (blue) is present. (D) In zebrafish trunk musculature, different fiber types are segregated, with the slowest fibers situated laterally, and fast fibers situated medially. (E) Key properties of fiber types, with the color code highlighting the graded shift from slow to fastest fibers. To simplify fiber typing, we operationally define these types by their myosin heavy chain (MYH) expression, however many other factors also distinguish fiber types. For instance, metabolic programs also contribute to muscle fiber phenotype.

Figure 2

Illustration of some of the known pathways that specify slow (red) or fast (blue) muscle fiber identity during developmental specification or during fiber plasticity. Although the pathways for plasticity are drawn separately from developmental pathways, some factors, such as SIX1, are used during both processes.

Figure 3

Schematic examples of factors that modulate MYOD1 activity in the regulation of fiber-type-specific gene expression. Protein factors are represented as colored circles binding to DNA regulatory regions of different genes involved in muscle fiber-type differentiation. References for these examples are provided in the text. These examples are highly schematized and are not comprehensive of all known factors that modulate MYOD1 activity. These examples are meant to represent a range of mechanisms, which are not mutually exclusive, for regulating MYOD1 activity.