Blocking protein restores strength, endurance in old mice, Stanford study finds

December 10, 2020

Blocking the activity of a single protein in old mice for one month restores mass and strength to the animals' withered muscles and helps them run longer on a treadmill, according to a study by researchers at the Stanford University School of Medicine. Conversely, increasing the expression of the protein in young mice causes their muscles to atrophy and weaken.

"The improvement is really quite dramatic" said Helen Blau, PhD, professor of microbiology and immunology. "The old mice are about 15% to 20% stronger after one month of treatment, and their muscle fibers look like young muscle. Considering that humans lose about 10% of muscle strength per decade after about age 50, this is quite remarkable."

The protein hasn't previously been implicated in aging. The researchers show that the amount of the protein, called 15-PGDH, is elevated in old muscle and is widely expressed in other old tissues. Experiments they conducted in human tissue raise hopes for a future treatment for the muscle weakness that occurs as people age.

Blau, the Donald E. and Delia B. Baxter Foundation Professor and director of the Baxter Laboratory for Stem Cell Biology, is the senior author of the study, which will be published online Dec. 10 in Science. Senior scientist Adelaida Palla, PhD, is the lead author.

Muscle loss in aging

Muscle loss during aging is known as sarcopenia, and it accounts for billions of dollars of health care expenditures in the United States each year as people lose the ability to care for themselves, experience more falls and become increasingly less mobile. It is due to changes in muscle structure and function: The muscle fibers shrink and the number and function of the cellular powerhouses known as mitochondria dwindle.

Blau and her colleagues have long been interested in understanding muscle function after muscle injury and in diseases like Duchenne muscular dystrophy. Previously, they found that a molecule called prostaglandin E2 can activate muscle stem cells that spring into action to repair damaged muscle fibers.

"We wondered whether this same pathway might also be important in aging," Blau said. "We were surprised to find that PGE2 not only augments the function of stem cells in regeneration, but also acts on mature muscle fibers. It has a potent dual role."

Prostaglandin E2 levels are regulated by 15-PGDH, which breaks down prostaglandin E2. The researchers used a highly sensitive version of mass spectrometry, a method for differentiating closely related molecules, to determine that compared with young mice, the 15-PGDH levels are elevated in the muscles of older animals, and the levels of prostaglandin E2 are lower.

They found a similar pattern of 15-PGDH expression in human muscle tissues, as those from people in their 70s and early 80s expressed higher levels than those from people in their mid-20s.

"We knew from our previous work that prostaglandin E2 was beneficial for regeneration of young muscles," Palla said. "But its short half-life makes it difficult to translate into a therapy. When we inhibited 15-PGDH, we observed a systemic elevation of prostaglandin E2 levels leading to a bodywide muscle improvement in aged mice."

Inhibiting 15-PGDH

The researchers administered a small molecule that blocks the activity of 15-PGDH to the mice daily for one month and assessed the effect of the treatment on the old and young animals.

"We found that, in old mice, even just partially inhibiting 15-PGDH restored prostaglandin E2 to physiological levels found in younger mice," Blau said. "The muscle fibers in these mice grew larger, and were stronger, than before the treatment. The mitochondria were more numerous, and looked and functioned like mitochondria in young muscle."

Treated animals were also able to run longer on a treadmill than untreated animals.

When Palla and her colleagues performed the reverse experiment -- overexpressing 15-PGDH in young mice -- the opposite occurred. The animals lost muscle tone and strength, and their muscle fibers shrank and became weaker, like those of old animals.

Finally, the researchers observed the effect of prostaglandin E2 on human myotubes --immature muscle fibers -- growing in a lab dish. They found that treating the myotubes with prostaglandin E2 caused them to increase in diameter, and protein synthesis in the myotubes was increased -- evidence that prostaglandin E2 worked directly on the muscle cells, not on other cells in the tissue microenvironment.

"It's clear that this one regulator, 15-PGDH, has a profound effect on muscle function," Blau said. "We're hopeful that these findings may lead to new ways to improve human health and impact the quality of life for many people. That's one of my main goals."

Blau and Palla are studying more about what controls the levels and activity of 15-PGDH during normal aging, and how it might affect the function of other tissues in the body.

"The mice perform better on a treadmill, but that requires more than just an increase in muscle strength," Blau said. "Other organ systems are involved -- the heart and lungs, for example. It suggests an overall improvement in the function of the whole animal."
-end-
Broadcast media contact:
Margarita Gallardo at
(650) 723-7897
(mjgallardo@stanford.edu)

Blau is a member of Stanford Bio-X, the Stanford Cardiovascular Institute, the Stanford Maternal and Child Health Research Institute, the Stanford Cancer Institute, and the Wu Tsai Neurosciences Institute at Stanford.

Other Stanford co-authors of the research are postdoctoral scholars Meenakshi Ravichandran, PhD, Christian Schürch, MD, PhD, and Yu Xin Wang, PhD; mass spectrometry specialist Ludmila Alexandrova, PhD; former senior scientist Andrew T.V. Ho, PhD; and research assistants Ann Yang, Peggy Kraft and Colin Holbrook.

The research was supported by the Baxter Foundation, the California Institute for Regenerative Medicine, the Li Ka Shing Foundation, the National Institutes of Health (grants 5R01AG02096115, 1RO1AG069858-01, RHG009674A, K99NS120278 and S10OD026962), the Canadian Institutes of Health Research and the Swiss National Science Foundation.

Blau, Palla, Ravichandran and Ho are inventors on patents related to 15-PGDH and licensed to Myoforte Therapeutics, of which Blau is a cofounder. Palla, Blau and Ho receive consulting fees and have equity and stock options from Myoforte Therapeutics.

The Stanford University School of Medicine consistently ranks among the nation's top medical schools, integrating research, medical education, patient care and community service. For more news about the school, please visit http://med.stanford.edu/school.html. The medical school is part of Stanford Medicine, which includes Stanford Health Care and Stanford Children's Health. For information about all three, please visit http://med.stanford.edu.

Stanford Medicine

Related Stem Cells Articles from Brightsurf:

SUTD researchers create heart cells from stem cells using 3D printing
SUTD researchers 3D printed a micro-scaled physical device to demonstrate a new level of control in the directed differentiation of stem cells, enhancing the production of cardiomyocytes.

More selective elimination of leukemia stem cells and blood stem cells
Hematopoietic stem cells from a healthy donor can help patients suffering from acute leukemia.

Computer simulations visualize how DNA is recognized to convert cells into stem cells
Researchers of the Hubrecht Institute (KNAW - The Netherlands) and the Max Planck Institute in Münster (Germany) have revealed how an essential protein helps to activate genomic DNA during the conversion of regular adult human cells into stem cells.

First events in stem cells becoming specialized cells needed for organ development
Cell biologists at the University of Toronto shed light on the very first step stem cells go through to turn into the specialized cells that make up organs.

Surprising research result: All immature cells can develop into stem cells
New sensational study conducted at the University of Copenhagen disproves traditional knowledge of stem cell development.

The development of brain stem cells into new nerve cells and why this can lead to cancer
Stem cells are true Jacks-of-all-trades of our bodies, as they can turn into the many different cell types of all organs.

Healthy blood stem cells have as many DNA mutations as leukemic cells
Researchers from the Princess Máxima Center for Pediatric Oncology have shown that the number of mutations in healthy and leukemic blood stem cells does not differ.

New method grows brain cells from stem cells quickly and efficiently
Researchers at Lund University in Sweden have developed a faster method to generate functional brain cells, called astrocytes, from embryonic stem cells.

NUS researchers confine mature cells to turn them into stem cells
Recent research led by Professor G.V. Shivashankar of the Mechanobiology Institute at the National University of Singapore and the FIRC Institute of Molecular Oncology in Italy, has revealed that mature cells can be reprogrammed into re-deployable stem cells without direct genetic modification -- by confining them to a defined geometric space for an extended period of time.

Researchers develop a new method for turning skin cells into pluripotent stem cells
Researchers at the University of Helsinki, Finland, and Karolinska Institutet, Sweden, have for the first time succeeded in converting human skin cells into pluripotent stem cells by activating the cell's own genes.

Read More: Stem Cells News and Stem Cells Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.