Artificial energy source for muscle
Synthesizing an alternative fuel for muscle could lead to medical
advances

Date:
July 13, 2020
Source:
University of Massachusetts Amherst
Summary:
Muscle physiologist sought an alternative energy source to
replace the body's usual one, adenosine triphosphate (ATP). Such
a source could control muscle activity, and might lead to new
muscle spasm-calming treatments in cerebral palsy, for example,
or activate or enhance skeletal muscle function in MS, ALS and
chronic heart failure. They report this month that they have made
a series of synthetic compounds to serve as alternative energy
sources for the muscle protein myosin.



FULL STORY ==========================================================================
A chemist and kinesiologist got on a bus, but this isn't the set-up to
a joke.

Instead, kinesiologist and lead author Ned Debold and chemist Dhandapani Venkataraman, "DV," began talking on their bus commute to the University
of Massachusetts Amherst and discovered their mutual interest in how
energy is converted from one form to another -- for Debold, in muscle
tissue and for DV, in solar cells.


========================================================================== Debold told the chemist how researchers have been seeking an alternative
energy source to replace the body's usual one, a molecule called adenosine triphosphate (ATP). Such a source could control muscle activity, and
might lead to new muscle spasm-calming treatments in cerebral palsy,
for example, or activate or enhance skeletal muscle function in MS,
ALS and chronic heart failure.

All are highly debilitating because the body has no way to fix them, says muscle physiologist Debold. It doesn't have good mechanisms to control -
- either inhibit or boost -- myosin function, the molecular motor that
drives movement.

As DV notes, the usual approach to seeking a new compound is to
systematically test each one among millions until one seems worth
followup -- the classic "needle in a haystack" approach. He says, "At
one point I suggested to Ned, 'Why don't we build the needle ourselves instead?' That started us on this interesting project that put together
people who would otherwise never work together." The two soon saw that
they would need someone to model interactions between the molecules DV
was making and the myosin molecules Debold was using to test them.

They invited computational chemist Jianhan Chen.

Chen explains, "We did computer modeling because experimentally it
is difficult to know how myosin might be using the molecules DV was synthesizing. We can use computer simulation to provide a detailed
picture at the molecular level to understand why these compounds might
have certain effects. This can provide insight into not only how myosin interacts with the current set of compounds, but also it can provide a
roadmap for DV to use to design new compounds that are even more effective
at altering myosin function." This month, the researchers report in the Biophysical Journal that they have made a series of synthetic compounds
to serve as alternative energy sources for the muscle protein myosin,
and that myosin can use this new energy source to generate force and
velocity. Mike Woodward from the Debold lab is the first author of
their paper and Xiaorong Liu from the Chen lab performed the computer simulation.

By using different isomers -- molecules with atoms in different
arrangements - - they were able to "effectively modulate, and even
inhibit, the activity of myosin," suggesting that changing the isomer
may offer a simple yet powerful approach to control molecular motor
function. With three isomers of the new ATP substitute, they show that
myosin's force- and motion-generating capacity can be dramatically
altered. "By correlating our experimental results with computation,
we show that each isomer exerts intrinsic control by affecting distinct
steps in myosin's mechano-chemical cycle." DV recalls, "My lab had never
made such types of compounds before, we had to learn a new chemistry;
my student Eric Ostrander worked on the synthesis." The new chemistry
involves sticking three phosphate groups onto a light-sensitive molecule, azobenzene, making what the researchers now call Azobenzene triphosphate,
he adds.

The next stage for the trio will be to map the process at various points
in myosin's biochemical cycle, Debold says. "In the muscle research field,
we still don't fully understand how myosin converts energy gain from
the food we eat into mechanical work. It's a question that lies at the
heart of understanding how muscles contract. By feeding myosin carefully designed alternative energy sources, we can understand how this complex molecular motor works. And along the way we are likely to reveal novel
targets and approaches to address a host of muscle related diseases."

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


========================================================================== Journal Reference:
1. Mike Woodward, Eric Ostrander, Seung P. Jeong, Xiarong Liu,
Brent Scott,
Matt Unger, Jianhan Chen, Dhandapani Venkataraman, Edward P. Debold.

Positional Isomers of a Non-Nucleoside Substrate Differentially
Affect Myosin Function. Biophysical Journal, 2020; DOI: 10.1016/
j.bpj.2020.06.024 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/07/200713165558.htm

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