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New clues to how muscle wasting occurs in people with cancer

Significant muscle wasting — or “cachexia” — occurs in about 80% of people with cancer and is responsible for about 30% of cancer deaths. It’s also associated with a reduced quality of life, problems tolerating chemotherapy and lower survival rates.

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Muscle wasting, or the loss of muscle tissue, is a common problem for people with cancer, but the precise mechanisms have long eluded doctors and scientists. Now, a new study led by Penn State researchers gives new clues to how muscle wasting happens on a cellular level.

Using a mouse model of ovarian cancer, the researchers found that cancer progression led to fewer skeletal muscle ribosomes — particles in the cell that make proteins. Because muscle mass is mainly determined by protein synthesis, having less ribosomes likely explains why muscles waste away in cancer.

Gustavo Nader, associate professor of kinesiology and physiology at Penn State, said the findings suggest a mechanism for muscle wasting that could be relevant not just for people with cancer, but other conditions as well.

“Loss of muscle mass is also associated with the aging process, malnutrition, and people with COVID-19 and HIV-AIDS, among others,” Nader said. “Not only is muscle wasting a common problem, but there’s currently no cure or treatment, either. But now that we understand the mechanism better, we can move forward with trying to find ways to reverse that mechanism.”

According to the researchers, significant muscle wasting — or “cachexia” — occurs in about 80% of people with cancer and is responsible for about 30% of cancer deaths. It’s also associated with a reduced quality of life, problems tolerating chemotherapy and lower survival rates. According to Nader, “cachexia is often the killer, not the tumor.”

Nader said that because there is no current cure or treatment for cachexia, it is vital for scientists to understand precisely how and why it happens. But while there has been a lot of research trying to understand and prevent the mechanism that causes muscles to waste, Nader and his team wanted to tackle the problem from a new angle.

“Most of the focus has been on protein degradation, where people have tried to block proteins from being chopped up, or degraded, in order to prevent the loss of muscle mass,” Nader said. “But many of those efforts have failed, and one reason may be because people forgot about the protein synthesis aspect of it, which is the process of creating new proteins. That’s what we tackled in this study.”

For the study, the team used a pre-clinical mouse model of ovarian cancer with significant muscle loss. By using mice, the researchers were able to study the progression of cancer cachexia over time which would be difficult to do with human patients.

After analyzing their results, the researchers found that mice with tumors experienced a rapid loss of muscle mass and a dramatic reduction in the ability to synthesize new proteins, which can be explained by a drop in the amount of ribosomes in their muscles.

“So we cracked the first layer of this problem, because we showed that there are less ribosomes and less protein synthesis,” Nader said.

Then, the researchers set out to explain why the number of ribosomes was decreased. After examining the ribosomal genes, they found that once a tumor was present, the expression of the ribosomal genes started to decrease until it reached a level that made it impossible for the muscles to produce enough ribosomes to maintain enough protein synthesis to prevent muscle loss.

Nader said that while more research is needed, he hopes the findings — recently published in the Federation of American Societies for Experimental Biology Journal — can eventually contribute to prevent people from losing muscle mass and function.

“If we can better understand how muscles make ribosomes, we will be able to find new treatments to both stimulate muscle growth and prevent muscle wasting,” Nader said. “This is especially important considering that current approaches to block tumor progression target the ribosomal production machinery, and because these drugs are given systemically, they will likely affect all tissues in the body and will also impair muscle building.”

Hyo-Gun Kim, Penn State; Joshua R. Huot, Indiana University School of Medicine; Fabrizio Pin, Indiana University School of Medicine; Bin Guo, Penn State; and Andrea Bonetto, Indiana University School of Medicine, also participated in this work.

Fitness

Want to be robust at 40-plus? Meeting minimum exercise guidelines won’t cut it

5 hours of moderate activity a week may be required to avoid midlife hypertension, UCSF-led study shows.

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Photo by Jonny Kennaugh from Unsplash.com

Young adults must step up their exercise routines to reduce their chances of developing high blood pressure or hypertension – a condition that may lead to heart attack and stroke, as well as dementia in later life.

Current guidelines indicate that adults should have a minimum of two-and-a-half hours of moderate intensity exercise each week, but a new study led by UCSF Benioff Children’s Hospitals reveals that boosting exercise to as much as five hours a week may protect against hypertension in midlife – particularly if it is sustained in one’s thirties, forties and fifties.

In the study publishing in American Journal of Preventive Medicine on April 15, researchers followed approximately 5,000 adults ages 18 to 30 for 30 years. The participants were asked about their exercise habits, medical history, smoking status and alcohol use. Blood pressure and weight were monitored, together with cholesterol and triglycerides.

Hypertension was noted if blood pressure was 130 over 80 mmHg, the threshold established in 2017 by the American College of Cardiology/American Heart Association.

The 5,115 participants had been enrolled by the Coronary Artery Risk Development in Young Adults (CARDIA) study and came from urban sites in Birmingham, Ala., Chicago, Minneapolis and Oakland, Calif. Approximately half the participants were Black (51.6 percent) and the remainder were White. Just under half (45.5 percent) were men.

Fitness Levels Fall Fast for Black Men Leading to More Hypertension

Among the four groups, who were categorized by race and gender, Black men were found to be the most active in early adulthood, exercising slightly more than White men and significantly more than Black women and White women. But by the time Black men reached age 60, exercise intake had slumped from a peak of approximately 560 exercise units to around 300 units, the equivalent to the minimum of two-and-a-half hours a week of moderate intensity exercise recommended by the U.S. Department of Health and Human Services. This was substantially less exercise than White men (approximately 430 units) and slightly more than White women (approximately 320 units). Of the four groups, Black women had the least exercise throughout the study period and saw declines over time to approximately 200 units.

“Although Black male youth may have high engagement in sports, socio-economic factors, neighborhood environments, and work or family responsibilities may prevent continued engagement in physical activity through adulthood,” said first author Jason Nagata, MD, of the UCSF Division of Adolescent and Young Adult Medicine. Additionally, Black men reported the highest rates of smoking, which may preclude physical activity over time, he noted.

Physical activity for White men declined in their twenties and thirties and stabilized at around age 40. For White women, physical activity hovered around 380 exercise units, dipping in their thirties and remaining constant to age 60.

Rates of hypertension mirrored this declining physical activity. Approximately 80-to-90 percent of Black men and women had hypertension by age 60, compared with just below 70 percent for White men and 50 percent for White women.

“Results from randomized controlled trials and observational studies have shown that exercise lowers blood pressure, suggesting that it may be important to focus on exercise as a way to lower blood pressure in all adults as they approach middle age,” said senior author Kirsten Bibbins-Domingo, MD, PhD, of the UCSF Department of Epidemiology and Biostatistics.

“Teenagers and those in their early twenties may be physically active but these patterns change with age. Our study suggests that maintaining physical activity during young adulthood – at higher levels than previously recommended – may be particularly important.”

More Exercise from Youth to Midlife Offers Best Protection Against Hypertension

When researchers looked at the 17.9 percent of participants who had moderate exercise for at least five hours a week during early adulthood – double the recommended minimum – they found that the likelihood of developing hypertension was 18 percent lower than for those who exercised less than five hours a week. The likelihood was even lower for the 11.7 percent of participants who maintained their exercise habits until age 60.

Patients should be asked about physical activity in the same way as they are routinely checked for blood pressure, glucose and lipid profiles, obesity and smoking, Nagata said, and intervention programs should be held at schools, colleges, churches, workplaces and community organizations. Black women have high rates of obesity and smoking, and low rates of physical activity, he said, and should be an important group for targeted intervention.

“Nearly half of our participants in young adulthood had suboptimal levels of physical activity, which was significantly associated with the onset of hypertension, indicating that we need to raise the minimum standard for physical activity,” Nagata said. “This might be especially the case after high school when opportunities for physical activity diminish as young adults transition to college, the workforce and parenthood, and leisure time is eroded.”

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Fitness

Childhood diet and exercise creates healthier, less anxious adults

Though diet and exercise are consistently recommended as ways to promote health, this study is the first to examine the long-lasting, combined effects of both factors when they are experienced early in life.

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Photo by Annie Spratt from Unsplash.com

Exercise and a healthy diet in childhood leads to adults with bigger brains and lower levels of anxiety, according to new UC Riverside research in mice.

Though diet and exercise are consistently recommended as ways to promote health, this study is the first to examine the long-lasting, combined effects of both factors when they are experienced early in life.

“Any time you go to the doctor with concerns about your weight, almost without fail, they recommend you exercise and eat less,” said study lead and UCR physiology doctoral student Marcell Cadney. “That’s why it’s surprising most studies only look at diet or exercise separately. In this study, we wanted to include both.”

The researchers determined that early-life exercise generally reduced anxious behaviors in adults. It also led to an increase in adult muscle and brain mass. When fed “Western” style diets high in fat and sugar, the mice not only became fatter, but also grew into adults that preferred unhealthy foods.

These findings have recently been published in the journal Physiology and Behavior. To obtain them, the researchers divided the young mice into four groups — those with access to exercise, those without access, those fed a standard, healthy diet and those who ate a Western diet.

Mice started on their diets immediately after weaning, and continued on them for three weeks, until they reached sexual maturity. After an additional eight weeks of “washout,” during which all mice were housed without wheels and on the healthy diet, the researchers did behavioral analysis, measured aerobic capacity, and levels of several different hormones.

One of those they measured, leptin, is produced by fat cells. It helps control body weight by increasing energy expenditure and signaling that less food is required. Early-life exercise increased adult leptin levels as well as fat mass in adult mice, regardless of the diet they ate.

Previously, the research team found that eating too much fat and sugar as a child can alter the microbiome for life, even if they later eat healthier. Going forward, the team plans to investigate whether fat or sugar is more responsible for the negative effects they measured in Western-diet-fed mice.

Together, both studies offer critical opportunities for health interventions in childhood habits.

“Our findings may be relevant for understanding the potential effects of activity reductions and dietary changes associated with obesity,” said UCR evolutionary physiologist Theodore Garland.

In other words, getting a jump start on health in the early years of life is extremely important, and interventions may be even more critical in the wake of the pandemic.

“During the COVID-19 lockdowns, particularly in the early months, kids got very little exercise. For many without access to a park or a backyard, school was their only source of physical activity,” Cadney said. “It is important we find solutions for these kids, possibly including extra attention as they grow into adults.”

Given that exercise was also shown to reduce adult anxiety, Cadney believes children who face these challenges may face unique physical and mental health issues as they become adults in the coming decade.

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Fitness

Exercise in mid-life won’t improve cognitive function in women

For middle-aged women, exercise has many health benefits, but it may not help maintain cognitive function over the long term, according to a new UCLA Health study.

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Photo by Karl Solano from Pexels.com

For middle-aged women, exercise has many health benefits, but it may not help maintain cognitive function over the long term, according to a new UCLA Health study. The study observed a diverse group of roughly 1,700 women over a 21-year period starting when the women’s average age was 45. In the study, women’s cognitive ability was tested in three key areas: cognitive processing speed (how fast the mind works); verbal memory (the ability to recall a story that they heard); and working memory (the ability to manipulate information).

The study was published in JAMA Network Open, and is one of the first to explore the longitudinal cognitive effects of physical activity in middle-aged women. The study found that over the 21 years, women’s cognitive processing speed declined by a total of 8%, or about 0.4% per year, and that verbal and working memory declined more slowly, dropping by 4% and 3%, respectively. After adjusting for other risk factors for cognitive aging, researchers found no association between physical activity and cognitive performance over time in the three cognitive areas tested.

“Our study showed that in midlife, women’s usual, self-selected exercise activity was not sufficient to slow cognitive aging,” said Gail Greendale, corresponding author of the study and professor of medicine and obstetrics and gynecology at the David Geffen School of Medicine at UCLA and research director of the Iris Cantor-UCLA Women’s Center.

However, Greendale points out that the study does not tell us whether increasing physical activity to higher levels might help preserve cognitive function. “We need more research on how to prevent cognitive aging during middle age — we just don’t know what works,” she said.

“In the meantime, the benefits of physical activity are great. While we work to figure out whether exercise is good for your brain, it’s important that we strive to maximize physical activity throughout the life span.”

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