Scientists identify compound that stimulates muscle cells in mice

UCLA researchers have identified a compound that can reproduce the effect of exercise in muscle cells in mice. The findings are published in the journal Cell Reports Medicine.

Normally, muscles get stronger as they are used, thanks to a series of chemical signals inside muscle cells. The newly identified compound activates those signals, which suggests that compounds like it could eventually be used to treat people with limb girdle muscular dystrophy, a form of adolescent-onset muscular dystrophy.

When muscles aren’t worked regularly, they gradually atrophy. (The phenomenon is familiar to anyone who’s had a cast on their leg for several weeks.) Fortunately, for people with healthy muscles, that deterioration is reversible. Muscle use stimulates chemical messengers inside the muscle cells that increase muscle mass and strength.

People with the muscle wasting disease limb girdle muscular dystrophy have a genetic defect that interferes with that chemical messenger, making their muscles unable to respond to exercise. No amount of exercise can trigger the signal to strengthen their muscles. Because the muscles never get the message, they gradually wither, and people with the disease end up in wheelchairs, almost completely paralyzed.

“It’s really dramatic. When these patients lose muscle, they struggle to gain it back,” said Melissa Spencer, the paper’s senior author and a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA.

The genetic defect responsible for limb girdle muscular dystrophy causes shortages of an enzyme in muscle cells called CaMK. CaMK is responsible for launching a chain of chemical signals that turns on genes to boost the cell’s ability to grow and metabolize fat, which is used as an energy source.

“CaMK activates genes that promote muscle growth and fat metabolism,” said Spencer, who is also a professor of neurology and the director of the neuromuscular program at the David Geffen School of Medicine at UCLA.

To find a drug that could help restore the signals related to CaMK, Spencer and her colleagues worked with Robert Damoiseaux, director of UCLA’s Molecular Shared Screening Resource, to screen more than 2,000 compounds to see which ones worked in lab-grown muscle cells. So far, they have tested 14 promising candidates in mice who had a genetic defect comparable to the one that causes limb girdle muscular dystrophy in people.

The testing identified a chemical compound called AMBMP that allowed mouse muscles to work and grow the way healthy muscle cells do.

“When we put the drug into mice, we found that it activated CaMK and restored all the properties we had observed as defective in our disease model,” Spencer said.

Spencer and her collaborators are planning further studies to understand how AMBMP affects CaMK and to identify similar compounds that could be more effective in humans.

UCLA neurology professor Vargehese John, associate researcher Irina Kramerova and staff research associate Jesus Campagna, co-authors of the new study, are already producing new compounds similar to AMBMP. Spencer and Kramerova will test those compounds in mice to determine the best drug candidate to advance to clinical trials.

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New developments for the treatment of muscle spasticity after stroke and nervous system defects

Chronic muscle spasticity after nervous system defects like stroke, traumatic brain and spinal cord injury, multiple sclerosis and painful low back pain affect more than 10% of the population, with a socioeconomic cost of about 500 billion USD. Currently, there is no adequate remedy to help these suffering people, which generates an immense medical need for a new generation antispastic drugs.

András Málnási-Csizmadia, co-founder of Motorpharma Ltd. and professor at Eötvös Loránd University in Hungary leads the development of a first-in-class drug candidate co-sponsored by Printnet Ltd. MPH-220 directly targets and inhibits the effector protein of muscle contraction, potentially by taking one pill per day. By contrast, current treatments have low efficacy and cause a wide range of side effects because they act indirectly, through the nervous system.

“We receive desperate emails from stroke survivors, who suffer from the excruciating symptoms of spasticity, asking if they could participate in our research. We work hard to accelerate the development of MPH-220 to alleviate these people’s chronic spasticity,” said Prof. Málnási-Csizmadia.

The mechanism of action of MPH-220 and preclinical studies are recently published in Cell. Dr. Máté Gyimesi, CSO of Motorpharma Ltd. highlighted: “The scientific challenge was to develop a chemical compound which discriminates between skeletal and cardiac muscle myosins, the motor proteins of these contractile systems. This feature of MPH-220 makes it highly specific and safe.”

Prof. James Spudich, co-founder of Cytokinetics, MyoKardia and Kainomyx, all companies developing drugs targeting cytoskeletal components, is also very excited about MPH-220 as a possible next generation muscle relaxant. “Cytokinetics and MyoKardia have shown that cardiac myosin is highly druggable, and both companies have potential drugs acting on cardiac myosin in late phase clinical trials. Skeletal myosin effectors, however, have not been reported. Motorpharma Ltd. has now developed a specific inhibitor of skeletal myosin, MPH-220, a drug candidate that may reduce the everyday painful spasticity for about 10% of the population that suffers from low back pain and neurological injury related diseases,” said Professor Spudich, former chair of Stanford medical school’s Biochemistry department, a Lasker awardee.

Drug development specifically targeting myosins is becoming a distinguished area, as indicated by last week’s acquisition of MyoKardia by Bristol-Myers Squibb Co. for 13.1 billion dollars in an all-cash deal, in the hope of marketing their experimental heart drug targeting cardiac myosin. This business activity shows the demand for start-up biotech companies such as Myokardia or Motorpharma.

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Scientists reveal relationship between Dek and Intron retention during muscle stem cells quiescence

Muscle stem cells, the reserve stem cell in the skeletal muscles, are responsible for muscle repair after damage. They are the ‘regenerative medicine’ to cure muscle diseases and muscle damage. In a healthy uninjured condition, muscle stem cells are in quiescence, a dormant state, to preserve them. Whenever there is muscle damage, they will wake up instantly and contribute themselves to building new muscles.

If this dormant state is loosely controlled, muscle stem cells will be wasted when there is no need for repair. If this dormant state is kept too tight, the muscle stem cells will not wake up when they are needed to contribute to muscle repair.

How muscle stem cells control this balance of quiescence remains a topic of heightened interest. Recently, a team of scientists at the Hong Kong University of Science and Technology revealed that intron detention (IR) is a key to the mechanism—when stem cells enter quiescence exit, Dek releases conserved introns, which allow the cell to be activated.

“Using skeletal muscle stem cells, also called satellite cells (SCs), we demonstrated prevalent intron retention (IR) in the transcriptome of quiescent SCs (QSCs),” said Prof. Tom Cheung, lead researcher of the team and SH Ho Associate Professor of Life Science at HKUST. “Intron-retained transcripts found in QSCs are essential for fundamental functions including RNA splicing, protein translation, cell-cycle entry, and lineage specification. Our analysis reveals that phosphorylated Dek protein modulates IR during SC quiescence exit.”

While Dek protein is not present in QSCs, Dek overexpression in vivo results in a global decrease of IR, quiescence dysregulation, premature differentiation of QSCs, and undermined muscle regeneration. The researchers also found in their IR analysis on hundreds of public RNA-seq data that IR is conserved among quiescent adult stem cells, which suggests that IR functions as a conserved post-transcriptional regulation mechanism that plays an important role during stem cell quiescence exit.

Their findings were published online in the journal Developmental Cell on June 4, 2020.

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