Piezo1 possible key to supporting muscle regeneration in Duchenne
Muscular Dystrophy

Date:
March 18, 2022
Source:
University of Pennsylvania School of Medicine
Summary:
Tracing the impact of a single protein, Piezo1, researchers found
that restoring it in muscles affected by Duchenne muscular dystrophy
could improve their ability to heal efficiently.



FULL STORY ==========================================================================
One protein, Piezo1, is key to marshalling muscle stem cells' unique
shapes and response to injuries, but it is in low supply in those
with Duchenne muscular dystrophy, according to a team at the Perelman
School of Medicine at the University of Pennsylvania. However, when they re-activated Piezo1, it allowed muscle stem cells in mice to return to
their normal, distinctly-shaped states so that they could repair broken
down, dystrophic muscles. These findings, published in Science Advances,
open the door to potential molecular-level treatments that may slow or
even halt the progression of muscular dystrophy.


==========================================================================
"We showed that muscle stem cells have a variety of extensions that are
used to sense their environment to respond to injuries, all of which is controlled by the protein Piezo1," said the study's lead author, Foteini Mourkioti, PhD, an assistant professor of Orthopaedic Surgery. "This is
in contrast to previous belief, which considered muscle stem cells to
be simply round and dormant in undamaged muscles." The Piezo1 protein
was identified just about a decade ago -- and netted a Nobel Prize last
year for those who uncovered it -- but its function in skeletal muscles
has been largely unknown. However, when Penn researchers examined it in
muscle stem cells, they found that it governed how the cells formed and coordinated their response to muscle damage.

Typically, muscle stem cells are called in by the body to repair muscle
tissue damage. Little has been known about how they actually do that
because most research on them has been done through point-in-time
observations in the lab.

But Mourkioti and her team were able to observe mice and discovered that
their muscle stem cells have protrusions they use to communicate with
each other that make them look similar to neurons (nerve cells).

Muscle stem cells also were found by Mourkioti's team to exist in a
balance of three different categories: responsive (or active) cells, intermediate cells, and sensory cells (which are closer to unassigned
stem cells). The more active the cell, the less protrusions they were
likely to have, while the sensory stem cells had more protrusions,
typically. Amid an injury, the researchers observed that muscle stem
cells focus on a rapid reaction from their responsive cells.

If an injury is big enough or takes enough time, intermediate cells and, eventually, sensory cells are brought in to address the damage and adjust
their form accordingly.

In effect, if muscle stem cells were organized like an army, the
responsive cells with fewer (or no) protrusions would be the shock troops
and the sensory cells with four or more protrusions are equivalent to
the reserves a general might call in if the front-line troops were being overwhelmed. As these reserve cells are called up, they shift form to
have fewer protrusions.



==========================================================================
In the army scenario, Piezo1 proteins would act as the general. These
proteins appeared to have the ability to dictate the form of the
protrusions on each cell.

Duchenne muscular dystrophy is a genetic disorder that is characterized
by the persistent breakdown of muscles and, thus, a constant need for
repair. The study found that mice with dystrophic muscles had markedly
lower levels of Piezo1 in their stem cells than those without the
condition. When the researchers observed muscle stem cell responses
to injuries in the dystrophic mice, they noticed significant delays
in moving from the sensory state to the active state. Cells also had protrusions that were thicker and longer, indicating that they weren't
being controlled properly.

Effectively, without an able general leading them, the muscle stem cells'
army falls into disarray, and it's overwhelmed by the volume of response
needed to repair the damage inflicted by Duchenne muscular dystrophy.

However, through these observations, Mourkioti and her team believe they discovered a key to turning the tide.

Through a small molecule treatment known as Yoda1, the channels for Piezo1
were reopened in the animals with dystrophic muscles. Through that,
they noticed the muscle stem cells returned to their normal structure
and function, with muscle regeneration appearing stronger than it had
been before.



========================================================================== "Even though progress has been made over the last decade on treatments
for Duchenne muscular dystrophy, current strategies still do not take
muscle stem cells into consideration," Mourkioti said. "But if we focus on minimizing stem cell exhaustion and maintaining the regenerative ability
of muscle stem cells, our work suggests that reactivating Piezo1 could
be key to that and used alone or in combination with other therapies."
Not only does this work have specific implications for Duchenne muscular dystrophy, but it could also benefit others with weak muscles resulting
from compromised stem cell abilities, including from natural aging.

Mourkioti and her team hope to study whether additional injected
treatments will be needed to sustain muscle stem cell activity. They also
hope to further examine Piezo1's functions in the body and do more tests
in pre-clinical dystrophic animal models with body masses comparable
to humans.

"Understanding the way that Piezo1 works better could be useful in
designing more accurate therapies," Mourkioti said.

This study was supported in part by grants from the National Aeronautics
and Space Administration (80NSSC19K1602) and the National Institutes
of Health/ National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01HL146662).


========================================================================== Story Source: Materials provided by University_of_Pennsylvania_School_of_Medicine. Note: Content may be
edited for style and length.


========================================================================== Journal Reference:
1. Nuoying Ma, Delia Chen, Ji-Hyung LeePaola Kuri, Edward Blake
Hernandez,
Jacob Kocan , Hamd Mahmood, Elisia D. Tichy, Panteleimon Rompolas
and Foteini Mourkioti. Piezo1 regulates the regenerative capacity
of skeletal muscles via orchestration of stem cell morphological
states. Science Advances, 2022 DOI: 10.1126/sciadv.abn0485 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220318161432.htm

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