Estrogen-related receptors could be the key to repairing energy metabolism and muscle fatigue. Mitochondrial dysfunction is difficult to treat, but recent findings from the Salk Institute show that a group of proteins called estrogen-related receptors could be a new and effective therapeutic target. These receptors play an important role in muscle cell metabolism, especially during exercise.

When our muscles need more energy, estrogen-related receptors can increase the number of mitochondria and enhance their energetic output within muscle cells. Developing a drug to boost these receptors could be a powerful way to restore energy supplies in people with metabolic disorders, such as muscular dystrophy.

Estrogen-related receptors are one branch of a family of proteins called nuclear hormone receptors. These receptors attach themselves to our DNA and control which genes get turned “on” or “off.” In the 1980s, researchers led by Ronald Evans discovered this family of proteins and recognized their role in energy metabolism. Now, they’ve learned that estrogen-related receptors are indispensable drivers of mitochondrial growth and activity in our muscles.

Exercise triggers mitochondrial biogenesis, wherein a cell increases the number of its mitochondria to produce more fuel. But exercising is difficult for people with muscular and metabolic disorders, so scientists have been looking for another way to stimulate this process. Estrogen-related receptors play a crucial role in this process, particularly during exercise.

Researchers deleted three different forms of estrogen-related receptors (alpha, beta, and gamma) in muscle tissues of mice and examined the resulting effects. They found that while the most abundant type was the alpha receptor, loss of just this one receptor had mild impacts on muscle tissue. However, if both alpha and gamma types were deleted, this led to serious impairments in muscle mitochondrial activity.

Exercise-induced mitochondrial biogenesis was driven by another protein called PGC1α, which relies on partner proteins to get the job done. Unlike PGC1α, estrogen-related receptors can bind directly to mitochondrial energetic genes and turn them “on,” making it a promising target for improving muscle’s mitochondrial performance.

“Our findings suggest that activating estrogen-related receptors could not only help fuel people’s muscles, but it could also have other beneficial effects across the whole body,” says first author Weiwei Fan. “Improving mitochondrial function and energy metabolism could help strengthen many different organ systems, including the brain and heart.”

Understanding how estrogen-related receptors function in muscle cells creates new opportunities to treat all parts of the body affected by mitochondrial dysfunction. Future research will continue to explore the function and regulation of both alpha- and gamma-type receptors, which may lead to other potential therapeutic targets.

The work was supported by several organizations, including the National Institutes of Health and the Larry L. Hillblom Foundation, Inc.

In a groundbreaking study led by Irish researchers, scientists have uncovered how a lipid-rich fluid in the abdomen, known as ascites, contributes to immune failure in advanced ovarian cancer. The findings shed new light on immune suppression in ovarian cancer and pave the way for innovative immunotherapy approaches.

According to the research, more than 70% of patients with ovarian cancer are diagnosed at an advanced stage, often accompanied by significant volumes of ascites fluid. This fluid not only supports the spread of cancer throughout the abdominal cavity but also severely impairs the body’s immune defenses. Understanding how ascites affects the immune system is crucial for developing better treatments that harness the power of the immune system to combat cancer.

Researchers from Trinity College Dublin and University College Dublin explored how ascites disrupts immune cell function, focusing on natural killer (NK) cells and T cells, key players in eliminating tumors. By analyzing the contents of ascites fluid from ovarian cancer patients, the team identified a group of fat molecules called phospholipids as primary drivers of this immune dysfunction.

Dr. Karen Slattery, Research Fellow at the Trinity Translational Medicine Institute, is the first author of the research article published in Science Immunology. She stated: “We discovered that these lipids interfere with NK cell metabolism and suppress their ability to kill cancer cells. Crucially, we found that blocking the uptake of these phospholipids into NK cells using a specific receptor blocker can restore their anti-tumour activity, which offers a compelling new target for therapeutic intervention.”

Prof. Lydia Lynch, formerly based in Trinity and now at Princeton University, is the senior author of the research article. She emphasized: “This study marks a significant advancement in ovarian cancer research, identifying a new mechanism underpinning immune failure and laying the foundation for new therapies that could restore immune function in these patients. By targeting the fat-induced suppression of immune cells, future treatments could empower the body’s own immune defenses to fight back and improve outcomes for ovarian cancer patients.”

The National Institutes of Health (NIH) has conducted a comprehensive analysis of cancer statistics for different age groups in the United States. The study reveals that between 2010 and 2019, the incidence rates of 14 cancer types increased among people under the age of 50. These cancer types include breast cancer, colorectal cancer, kidney cancer, uterine cancer, and others.

Lead investigator Meredith Shiels, Ph.D., notes that this study provides a starting point for understanding which cancers are increasing among individuals under 50. The causes of these increases are likely to be specific to each type of cancer, including changes in cancer risk factors, screening or detection methods, and clinical diagnosis or coding.

The researchers analyzed incidence and mortality trends for 33 cancer types using data from the Centers for Disease Control and Prevention’s United States Cancer Statistics database and national death certificate data. They examined six age groups: three early-onset (15-29 years, 20-39 years, and 40-49 years) and three older-onset (50-59 years, 60-69 years, and 70-79 years).

The study found that the incidence of nine cancer types increased in at least one of the younger age groups, including female breast, colorectal, kidney, testicular, uterine, pancreatic, and three types of lymphoma. Although death rates did not increase in early-onset age groups for most of these cancers, researchers observed concerning increases in rates of colorectal and uterine cancer deaths at younger ages.

Only five cancer types increased in incidence among one of the younger age groups but not among any of the older age groups: melanoma, cervical cancer, stomach cancer, myeloma, and cancers of the bones and joints.

To better understand the magnitude of these increases, researchers estimated how many additional people were diagnosed with early-onset cancers in 2019 compared to expected diagnoses based on rates in 2010. The largest absolute increases were seen for female breast cancer (4,800 additional cases), followed by colorectal (2,100), kidney (1,800), uterine (1,200), and pancreatic cancers (500).

The researchers speculate that risk factors such as increasing obesity may have contributed to some of the increases in early-onset cancer incidence. Changes in cancer screening guidelines, advances in imaging technologies, and increased surveillance of high-risk individuals may also have led to earlier cancer diagnoses, potentially contributing to rising rates among younger age groups.

To more fully understand and address these increasing rates, future studies should examine trends in early-onset cancers across demographics and geography in the U.S. and internationally. Additional research is also needed to better understand the risk factors that are particularly relevant to younger people.