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June 21, 2021

Stopping muscles fatigue

T-CiRA's projects of Hidetoshi Sakurai and Akitsu Hotta use iPS cells to model the muscle fatigue in Duchenne muscular dystrophy and find preventative drugs.

Our body weight mostly comes from our more than 600 muscles. Muscular dystrophies can cause the loss of some or all of these muscles, including those responsible for breathing and swallowing. The loss of muscle is why patients become weak and eventually die. Capturing the muscle weakness in the laboratory is essential for developing drugs to treat these diseases. A new study led by CiRA Accociate Professor Hidetoshi Sakurai and Junior Associate Professor Akitsu Hotta, both of whom are also principal investigators of Takeda-CiRA Joint Program for iPS Cell Applications (T-CiRA), shows how iPS cell technology can accurately capture muscle decline in patients with Duchenne muscular dystrophy (DMD).

DMD is the most common and one of the severest forms of muscular dystrophy It is the result of a mutation in the dystrophin protein. Dystrophin acts a shock absorber. Without it, movement grinds on the muscle, causing the muscle to wear away at a rate too fast for it to recover.

"The decline in muscle performance and rise in muscle fatigue are seen in all DMD patients, regardless of their age or condition. However, there are no good laboratory models that capture these properties. Therefore, we don't know the relationship between muscle fatigue, dystrophin deficiency and disease progression," said Sakurai, who uses iPS cells to study DMD.

To answer this question, the researchers prepared iPS cells from DMD patients and then differentiated the cells into myotubes. These iPS-myotubes were then exposed to electrical-field stimulation. Muscles are electro-mechanical transducers that take an electrical signal and convert it into a force. Electrical-field stimulation, explained Sakurai, is commonly used to stimulate this transduction in myotubes in the lab, but has not been used to study diseases like DMD.

"Electrical-field stimulation matures the myotubes so that they behave like muscle in the human body. Maturation is necessary to recapitulate the contractile properties," he said.

Although all DMD is caused by a dystrophin mutation, different dystrophin mutations have been found in different patients. Therefore, iPS cells were prepared from patients showing variable mutations. These mutations were also corrected in the iPS cells using CRISPR-Cas9 gene editing technology to see how the response to electrical-field stimulation changed.

Early on, myotubes made from uncorrected iPS cells could perform equally to their corrected counterparts, but gradually they showed functional deterioration indicative of fatigue.

Having confirmed they could capture the poor muscle performance seen in patients, Sakurai and colleagues then tested a number of drugs on the cells.

"Our results indicated that there was a deficiency in calcium signaling," said Sakurai. Calcium is a fundamental factor that acts as an electrical signal for muscle contractions in the human body. "We therefore tested commercially available calcium modulators and found that some could sustain muscle performance."

The ability to mimic the progressive muscle fatigue in DMD patients in the lab is expected to contribute to drug development that can help patients preserve muscle performance over a longer period of time.

Paper Details
  • Journal: Cell Reports Medicine
  • Title: A muscle fatigue-like contractile decline was recapitulated using skeletal myotubes from Duchenne muscular dystrophy patient-derived iPSCs
  • Authors: Tomoya Uchimura1,2, Toshifumi Asano3,4, Takao Nakata3,4, Akitsu Hotta1,2,
    and Hidetoshi Sakurai1,2
  • Author Affiliations:
    1. Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
    2. Takeda-CiRA Joint program (T-CiRA), Fujisawa, Japan
    3. Department of Cell Biology, Graduate School of Medical and Dental Science, Tokyo Medical and Dental University, Tokyo, Japan
    4. The Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, Japan
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