Protein Family Is Key for Powerful Muscle Fiber Generation

A protein family’s role in the regulation of fast-twitch muscle fibers – those involved in fast and powerful movements – has been identified by scientists at the University of Tsukuba. The research is published in Cell Reports.

Slow- and fast-twitch muscle fibers

The musculature of the human body comprises different types of myofibers, or muscle fibers. After birth, these muscle fibers are “plastic” – i.e., their growth and development can be shaped by factors such as exercise, aging, immobilization and, if you happen to be an astronaut, spaceflight.

Myofibers are broadly categorized as either slow-twitch (Type 1 myofibers), or fast-twitch (Type 2 myofibers). The latter can be further subclassified as either Type 2a, Type 2x or Type 2b depending on the expression of myosin heavy chain (MYH) proteins, motor proteins that convert the energy derived from the hydrolysis of ATP into mechanical force.

Slow-twitch fibers are mitochondria-rich and have a high oxidative metabolism, supporting endurance activities including long-distance running. Fast-twitch fibers, in comparison, are utilized for short and powerful movements, such as weightlifting.

While research has demonstrated the factors and pathways implicated in the formation of slow-twitch fibers, less is known about the transcription factors required for fast-twitch fiber generation. The new study has uncovered the role that a group of proteins – known as the Maf transcription factor family – plays in this process.

Maf protein central to regulation of slow-to-fast muscle fiber transition

Long durations of reduced activity, as is experienced by astronauts in space for example, encourages slow-to-fast muscle fiber transition. The research team had previously demonstrated that Maf expression is impacted by gravitational load variation prior to the new study. “We previously developed a multiple artificial gravity system (MARS) on the international space station (ISS), enabling us to study the effect of various gravitational loads on mammals. Through whole-transcriptome analysis of skeletal muscles in mice exposed to microgravity or artificial gravity (1 g) in MARS, we found that the expression of the large Maf transcription factor family responded dynamically to mechanical stimuli,” the researchers write.

"This seemed to indicate that the large Mafs are induced in muscles experiencing slow-to-fast muscle fiber transition," says senior author Professor Satoru Takahashi.

Expanding on this work, the researchers designed a triple knockout (TKO) mouse model, where three Maf proteins, Mafa, Mafb and Maf (also known as c-Maf) were inactivated. The mice demonstrated a significant reduction in fast-twitch muscle mass in contrast to control mice, with no apparent impact on slow-twitch muscle mass. "The TKO mice had significantly lower average grip strength, but could run longer on a treadmill than control mice, implying that more fast-to-slow muscle fiber conversion had occurred in the absence of large Maf expression," says Professor Ryo Fujita, expert in tissue regeneration and lead author of the study.

The TKO mice were also found to lack Type 2b fast-twitch fibers, but when the researchers overexpressed Mafs in the leg muscle of mice, a significant increase in Type 2b fibers occurred.  

A potential treatment target for muscular disorders?

Discussing the limitations of the study, the research team note that the gene deletions occur at the embryonic phase of muscle development in their mouse model. “Therefore, whether the large Maf family plays a functional role in the adult post-natal myofibers was remains to be addressed,” they state.

However, their data could offer new insights on how slow-to-fast muscle fiber transition occurs in mammals and may support further research identifying novel therapeutic targets for muscular disorders.

“Collectively, our data identify large Mafs as robust transcriptional elements that directly regulate Type 2b myofibers during development and adaptation of skeletal muscle,” the research team conclude.

Reference: Sadaki S, Fujita R, Hayashi T, et al. Large Maf transcription factor family is a major regulator of fast type IIb myofiber determination. Cell Reports. 2023;42(4). doi: 10.1016/j.celrep.2023.112289.

This article is a rework of a press release issued by the University of Tsukuba. Material has been edited for length and content.