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Type IIb fast-twitch myofibers, known for their rapid contraction speed, are plentiful in small mammals but have largely diminished in humans. Researchers at University of Tsukuba have discovered that the overexpression of a protein called the large Maf group transcription factor in human muscle cells can reactivate the dormant "Type IIb fast-twitch muscle program."

Tsukuba, Japan—Muscle fibers, which constitute skeletal muscle, are classified into two main types: slow-twitch (Type I, red muscle) and fast-twitch (Type II, white muscle). Slow-twitch fibers are ideal for endurance activities such as marathons, whereas fast-twitch fibers support quick, powerful movements such as sprinting or jumping. A decrease in fast-twitch fibers directly contributes to age-related muscle weakness (sarcopenia) and physical dysfunction.

Fast-twitch fibers are further divided into three subtypes: IIa, IIx, and IIb. Of these, Type IIb fibers contract the fastest and generate the greatest power. The research team previously identified a group of proteins known as the large MAF family transcription factors (MAFA, MAFB, MAF) as key regulatory factors in the formation of Type IIb muscle fibers in mice. Small mammals, such as mice, have abundant Type IIb fast-twitch muscle fibers that express myosin IIb (encoded by the MYH4 gene), responsible for their rapid contractions. By contrast, large mammals, including humans, have largely lost Type IIb fast-twitch fibers, although the reason for this decline has remained unclear.

Focusing on the large MAF family transcription factors identified in mice, the research team found that these factors act as direct switches to induce MYH4 expression. Overexpressing these transcription factors in human and bovine muscle cells reactivated the dormant "Type IIb fast-twitch program," leading to increased MYH4 expression, which had previously been minimal. This also resulted in improved glycolytic capacity, enhancing the cells' ability to break down sugar for energy. Moreover, analysis of human skeletal muscle biopsy samples showed higher expression levels of MAFA, MAF, and MYH4 in athletes engaged in power training. This suggests that large MAF family transcription factors may contribute to the proportion of fast-twitch fibers and overall exercise capacity in humans.

These findings mark the first identification of a mechanism that activates the dormant fast-twitch function in human muscle. This discovery has the potential to lead to new approaches for preventing and improving sarcopenia, enhancing athletic performance, and even expanding functional capabilities in humans.

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AMED-CREST grant JP23gm171008h (RF, ST). Japan Society for the Promotion of Science (JSPS) grants 24K02876 (RF), 24K22244 (RF), and 21K19195 (KO). Takeda Science Foundation (RF). Mochida Memorial Foundation for Medical and Pharmaceutical Research grant (RF). JST FOREST program JPMJFR234V (RF). Russian Science Foundation grant 24-15-00413 (IIA). Acceleration Program for Intractable Diseases Research utilizing Disease-specific iPS cells grant JP20bm0804025 (HS). JSPS Research Fellowships for Young Scientists grant 23KJ0287 (SS).

Original Paper

Title of original paper:

Large Maf Transcription Factors Reawaken Evolutionarily Dormant Fast-Glycolytic Type IIb Myofibers in Human Skeletal Muscle

Journal:

Skeletal Muscle

DOI:

10.1186/s13395-025-00391-5

Correspondence

Associate Professor FUJITA Ryo
Division of Regenerative Medicine, Transborder Medical Research Center / Institute of Medicine, University of Tsukuba

Related Link

Institute of Medicine
Transborder Medical Research Center