Tag: muscle loss

Categories : CancerTags :

New Trial of Drug Shows Promise in Combating Cancer-caused Cachexia

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Researchers discovered a drug that safely and effectively helped cancer patients when they suffered from cachexia, a common condition related to cancer that involves weight loss and muscle wasting.

The results of the randomised phase 2 clinical trial, which included 187 individuals who experienced cachexia with pancreatic (32%), colorectal (29%) or non–small-cell lung (40%) cancer, appear in the New England Journal of Medicine.  Richard Dunne, MD, MS, a Wilmot Cancer Institute oncologist and cachexia expert was part of the large group of investigators who ran the nationwide clinical trial.

Cachexia involves loss of appetite and weight, muscle-wasting, fatigue, and weakness. It affects more than 50% of people who have cancer, and currently there are no FDA-approved treatments.

Scientists discovered that the monoclonal antibody ponsegromab blocks a hormone known as GDF-15 that regulates appetite and body weight. The patients in the trial had elevated levels of GDF-15, a primary driver of cachexia, and ponsegromab improved many aspects of cachexia and its symptoms.

Patients were randomised to receive ponsegromab at doses of 100mg, 200mg, or 400 mg, or to receive placebo. At 12 weeks, patients in the ponsegromab groups had significantly greater weight gain than those in the placebo group, with a median between-group difference of 1.22 kg in the 100mg group, 1.92 in the 200mg group, and 2.81 in the 400mg group. Improvements were observed across measures of appetite and cachexia symptoms, along with physical activity, in the 400mg ponsegromab group relative to placebo.

Drugmaker Pfizer supported the study, and released this news. Side effects were minimal, Dunne said, and in fact ponsegromab appeared to be safer than common appetite stimulants used by cachexia patients.

“This is super exciting,” said Dunne, an associate professor of Medicine at the University of Rochester Medical Center. “This study is an important step in providing treatment for the hundreds of thousands of patients who suffer from poor quality of life due to cachexia.”

Several academic medical centres participated in the clinical research, which was led by John D. Groarke, MB, BCh, MPH, at Pfizer. Investigators are continuing to study GDF-15 and the importance of the biomarker in several types of cancer. Other clinical trials are also testing additional cachexia treatments that do not target the GDF-15 pathway.

Source: University of Rochester Medical Center

Categories : Regenerative MedicineTags :

Breakthrough in Understanding Skeletal Muscle Regeneration

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Newly published research from the University of Houston College of Pharmacy identifies key mechanisms of skeletal muscle regeneration and growth of muscles following resistance exercise. The findings, published in EMBO Reports, open the door to the development of targeted therapies for various muscle disorders, like Muscular Dystrophy, which affect millions of people worldwide.

When it comes to muscles and muscle disorders, the importance of a discovery like this cannot be overstated.

Muscles’ regenerative powers

Skeletal muscles are formed during embryonic development by the fusion of hundreds of specialised cells called myoblasts. Adult skeletal muscles maintain regenerative capacity, which is attributed to the presence of muscle stem cells, named satellite cells.

After injury, satellite cells undergo several rounds of proliferation followed by their differentiation into myoblasts. These myoblasts once again fuse with each other and to injured myofibres to accomplish muscle regeneration.

In many muscular disorders, this intrinsic capacity of muscles to regenerate is diminished resulting in the loss of muscle mass and function.

Key signalling protein

UH researchers found that Inositol-requiring enzyme 1, a key signalling protein, is essential for myoblast fusion during muscle formation and growth.

“During muscle regeneration, IRE1 augments the activity of X-box binding protein 1 which in turn stimulates the gene expression of multiple transmembrane proteins required for myoblast fusion,” reports Ashok Kumar, professor of pharmacy in the Department of Pharmacological and Pharmaceutical Sciences.

According to researchers, increasing the levels of IRE1 or XBP1 in muscle stem cells outside the body, followed by their injection in patients’ muscle tissues will improve muscle repair and reduce the severity of disease.

“We also found that augmenting the levels of IRE1α or XBP1 in myoblasts leads to the formation of myotubes (muscle cells) having an increased diameter,” said Kumar.

That increase in diameter can be significant.

“Size is very important for muscle. Muscle grows only in size, not in number,” said Aniket Joshi, a graduate student in Kumar’s lab and first author on the article. “Muscular people have larger muscle cells. Larger muscles generally work better- can lift more weight, run and walk faster, and improve overall metabolism of the body and prevent various diseases, such as type II diabetes.”

Flexing their muscles

This new research is not the first flex for Kumar’s team. In 2021, research from Kumar’s lab published in the ELife journal described the role of the IRE1α/XBP1 signaling axis in regeneration of healthy skeletal muscle after acute injury and in models of Duchenne Muscular Dystrophy. In this study, they found that IRE1α/XBP1 signaling axis also plays an important cell autonomous role in satellite cells.

Source: University of Houston

Categories : Diet and NutritionTags :

Time to Debunk Four Persistent Myths about Intermittent Fasting

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In a new article published in Nature Reviews Endocrinology, researchers at the University of Illinois Chicago debunk four common myths about the safety of intermittent fasting. 

Intermittent fasting as a weight loss method has grown increasingly popular, with a large body of research demonstrating its safety. Despite this, several myths about fasting have spread among clinicians, journalists and the general public: that fasting can lead to a poor diet or loss of lean muscle mass, cause eating disorders, or decrease sex hormones. 

In a new commentary, UIC researchers debunk each of these. They base their conclusions on clinical studies, some of which they conducted and some done by others. 

“I’ve been studying intermittent fasting for 20 years, and I’m constantly asked if the diets are safe,” said lead author Krista Varady, professor of kinesiology and nutrition at UIC. “There is a lot of misinformation out there. However, those ideas are not based on science; they’re just based on personal opinion.”  

There are two main types of intermittent fasting. With alternate-day eating, people alternate between days of eating a very small number of calories and days of eating what they want. With time-restricted eating, people eat what they want during a four- to 10-hour window each day, then don’t eat during the rest of the day. The researchers conclude both types are safe despite the popular myths.

Their conclusions: 

Intermittent fasting does not lead to a poor diet: The researchers point to studies showing the intake of sugar, saturated fat, cholesterol, fibre, sodium and caffeine do not change during fasting compared with before a fast. And the percentage of energy consumed in carbohydrates, protein and fat doesn’t change, either.  

Intermittent fasting does not cause eating disorders: None of the studies show that fasting caused participants to develop an eating disorder. However, all the studies screened out participants who had a history of eating disorders, and the researchers say that those with a history of eating disorders should not try intermittent fasting. They also urge paediatricians to be cautious when monitoring obese adolescents if they start fasting, because this group has a high risk of developing eating disorders. 

Intermittent fasting does not cause excessive loss of lean muscle mass: The studies show that people lose the same amount of lean muscle mass whether they’re losing weight by fasting or with a different diet. In both cases, resistance training and increased protein intake can counteract the loss of lean muscle. 

Intermittent fasting does not affect sex hormones: Despite concerns about fertility and libido, neither oestrogen, testosterone nor other related hormones are affected by fasting, the researchers said. 

Source: University of Illinois Chicago

Categories : Ageing Metabolic DisordersTags :

Metformin Also Seems to Protect Against Muscle Atrophy and Fibrosis

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Diabetes and muscle function might seem like they don’t have much to do with each other. But University of Utah Health researchers have discovered that metformin can also prevent muscle atrophy and muscular fibrosis – which can help the elderly bounce back faster from injury or illness. Their findings were published in the journal Aging Cell.

Metformin, the researchers found, actually has surprising applications on a cellular level. It can target senescent cells which impact muscle function. Senescent cells secrete factors associated with inflammation that may underlie fibrotic tissue, a hardening or scarring of tissues. They also discovered that metformin also reduces muscle atrophy.

“We’re interested in clinical application of this research,” says Micah Drummond, PhD, senior author of the study and professor of physical therapy and athletic training at the College of Health. “For example, knee surgeries in the elderly are notoriously hard to recover from. If we give a metformin-type agent during the recovery period, could we help the muscles get back to normal faster?”

Reinvigorating muscle recovery

Ageing comes with the risks of falls, hospitalisation, or developing chronic disease, which are more likely with muscle disuse. The research team wanted to find a therapeutic solution that could properly target both disuse atrophy and muscle recovery.

There’s an optimal level of senescent cells that are beneficial, no matter your age. In younger, healthier people, short-term senescence is required for a proper recovery from injury, and completely blocking the senescent effect impedes the body’s efforts to heal. Typically, a younger person can bounce back more easily after muscle disuse without the use of an intervention such as Metformin.

“In the case of aging, we know that there’s immune dysfunction,” says Drummond. “As you get older, it becomes harder for your body to clear senescent cells and they accumulate. That’s one reason recovery is much slower for the elderly after periods of disuse.”

Metformin’s anti-senescent properties have been demonstrated through pre-clinical studies. To test the intervention in humans, the team recruited 20 healthy male and female older adults for a multi-week study. They had participants undergo a muscle biopsy and MRI before the intervention, which involved five days of bed rest. One group of 10 received metformin and the other 10 received placebo pills during a two-week run-in period, then each group continued the placebo or metformin treatment during bed rest.

After the bed rest, participants received another muscle biopsy and MRI, then ceased treatments. All patients completed a seven-day re-ambulation period followed by a final muscle biopsy.

“We saw two things in our study,” Drummond says. “When participants took Metformin during a bed rest, they had less muscle atrophy. During the recovery period, their muscles also had less fibrosis or excessive collagen. That build-up can make it harder for the muscle to properly function.”

Tying these results to senescence, the research team examined muscle biopsies from study participants. They found that the participants who took Metformin had fewer markers of cellular senescence.

“This is the first paper that has made the direct connection between a therapy targeting cellular senescence and improved muscle recovery following disuse in aging,” says lead author Jonathan Petrocelli, PhD He explains that metformin helps muscle cells better remodel and repair tissue during periods of recovery after inactivity.

“Our real goal is to have patients maintain their muscle mass and function as they age, because atrophy and weakness are some of the strongest predictors of disease development and death,” he says.

Drummond’s team is following up on these findings by examining combining the drug with leucine, an amino acid that promotes growth and could accelerate recovery even further. They’ve already demonstrated the potency of this combination in preclinical animal studies.

“Metformin is cheap, effective and quite safe, so it’s exciting to see that we can use it to accelerate recovery for older individuals,” adds Drummond.

Source: University of Utah Health

Categories : AgeingTags :

The Secret of ‘Rejuvenating’ Blood Transfusions Between Mice

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Researchers have identified an important mediator of youthfulness in mouse muscle, which explains the ‘rejuvenating’ blood transfusions effect between young and old mice. The discovery could also lead to new therapies for age-related muscle loss.

Published in Nature Aging, the study showed that circulating shuttles called extracellular vesicles, or EVs, deliver genetic instructions for the longevity protein known as Klotho to muscle cells. Reduced muscle function and repair in old mice may be driven by aged EVs, which carry fewer instructions than those in young animals.

The findings help further as to understanding why muscle regeneration capacity diminishes with age.

“We’re really excited about this research for a couple of reasons,” said senior author Dr Fabrisia Ambrosio. “In one way, it helps us understand the basic biology of how muscle regeneration works and how it fails to work as we age. Then, taking that information to the next step, we can think about using extracellular vesicles as therapeutics to counteract these age-related defects.”

Decades of research have shown that when old mice are given blood from young mice, youthful features are restored to many cells and tissues. But until now, it was unclear which components of young blood confer these rejuvenating effects.

“Amrita Sahu releaseWe wondered if extracellular vesicles might contribute to muscle regeneration because these couriers travel between cells via the blood and other bodily fluids,” said lead author Dr Amrita Sahu. “Like a message in a bottle, EVs deliver information to target cells.”

Ambrosio and her team collected serum from young mice and injected it into aged mice with injured muscle. Mice that received young serum showed enhanced muscle regeneration and functional recovery compared to those that received a placebo treatment, but the serum’s restorative properties were lost when EVs were removed, indicating that it is these vesicles which deliver the beneficial effects of young blood.

The researchers then found that EVs deliver genetic instructions, or mRNA, encoding the anti-ageing protein Klotho to muscle progenitor cells, important stem cells for muscle regeneration. EVs collected from old mice carried fewer copies of Klotho instructions than those from young mice, causing muscle progenitor cells to produce less of this protein.

With advancing age, muscle doesn’t recover from damage as well because scar tissue is laid down. In earlier work, Ambrosio and her team showed that Klotho is an important regulator of regenerative capacity in muscle progenitor cells and that this protein declines with age.

The new study shows for the first time that age-related shifts in EV cargo contribute to depleted Klotho in aged stem cells, suggesting that EVs could be developed into novel therapies for healing damaged muscle tissue.

“EVs may be beneficial for boosting regenerative capacity of muscle in older individuals and improving functional recovery after an injury,” said Ambrosio. “One of the ideas we’re really excited about is engineering EVs with specific cargoes, so that we can dictate the responses of target cells.”

Beyond muscles, EVs also could help reverse other effects of ageing. Previous work has demonstrated that young blood can boost cognitive performance of aged mice.


Source: University of Pittsburgh

Categories : GeneticsTags :

Muscle Atrophy Gene Identified from Mice Sent into Space

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Dragon cargo capsule arriving at the International Space Station. Image by SpaceX-Imagery from Pixabay

Researchers from the University of Tsukuba have found a new gene involved in muscle atrophy when they sent mice into space to explore effects of weightlessness on skeletal muscles.

Extended periods of skeletal muscle inactivity or mechanical unloading (bed rest, immobilisation, spaceflight and reduced step) can result in a significant loss of muscle mass and strength which ultimately lead to muscle atrophy. Spaceflight is one of the leading models of understanding muscle atrophy from disuse.

As the molecular and cellular mechanisms involved in disuse skeletal muscle atrophy have been studied, several different signaling pathways have been studied to understand their regulatory role in this process. However, large gaps exist in the understanding of the regulatory mechanisms involved, as well as their functional significance.

Prior studies examining the effects of reduced gravity on muscle mass and function have used a ground control group which cannot be directly compared to the space experimental group. Researchers from the University of Tsukuba set out to explore the effects of gravity in mice subjected to the same housing conditions, such as the stresses of launch, landing and cosmic radiation. “In humans, spaceflight causes muscle atrophy and can lead to serious medical problems after return to Earth” says senior author Professor Satoru Takahashi. “This study was designed based on the critical need to understand the molecular mechanisms through which muscle atrophy occurs in conditions of microgravity and artificial gravity.”

Two groups of six mice each were housed onboard the International Space Station for 35 days. One group was subjected to artificial gravity (1g) and the other was left in microgravity. All mice were returned to Earth aboard a Dragon capsule and the team compared the effects of the different onboard environments on skeletal muscles. “To understand what was happening inside the muscles and cells, at the molecular level, we examined the muscle fibers. Our results show that artificial gravity prevents the changes observed in mice subjected to microgravity, including muscle atrophy and changes in gene expression,” explained Prof Takahashi. 

Transcriptional analysis of gene expression showed that the artificial gravity environment prevented altered expression of atrophy-related genes, and also identified other genes possibly associated with atrophy. Specifically, a gene called Cacng1 was identified as possibly having a functional role in myotube atrophy, which previously had no known function, and was shown to have increased activity when muscle atrophy was present.

When muscle fibres were cultured in vitro, ones which had Cacng1 expression upregulated were decreased in diameter by 27.5%. A similar effect was seen in newborn mice with upregulated Cacng1.

This work validated the use of 1g artificial gravity environments in spaceflight for examining the effects of microgravity in muscles. These studies add to the body of knowledge surrounding the mechanisms of muscle atrophy, possibly improving the treatment of related diseases.

Source: Tsukuba University

Journal information: Okada, R., et al. (2021) Transcriptome analysis of gravitational effects on mouse skeletal muscles under microgravity and artificial 1 g onboard environment. Scientific Reports. doi.org/10.1038/s41598-021-88392-4.

Categories : CancerTags :

Colorectal Cancer Risk Is Not Reduced by Maintaining Weight

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A new study shows that, contrary to conventional wisdom, significant weight changes before treatment do not by themselves increase the mortality risk from colorectal cancer, rather it is changes in body composition.

In a population-based cohort study, for every 5% loss of body weight after colorectal cancer diagnosis had a 41% increased mortality risk.

“The conventional wisdom has been that colorectal cancer patients should avoid losing or gaining weight during treatment,”  explained Dr Justin C Brown, Assistant Professor and Director of Cancer Metabolism Program, Pennington Biomedical Research Center. “But maintaining your weight does not mean your body composition remains the same. Muscle can change quite dramatically, and those changes are associated with a much higher risk of death.”

“This study highlights how body composition can have a powerful impact on long-term health. We at Pennington Biomedical are committed to conducting innovative research to enable cancer survivors around the world to achieve their best possible health,” said Dr John Kirwan, Executive Director.

The study enrolled 1921 patients with stage I-III colorectal cancer, measuring skeletal muscle and body weight at diagnosis and then an average of 15 months later. The definition of stable body weight was a change of less than 5% of weight at diagnosis.

Researchers found having a stable body weight hides changes in skeletal muscle loss. Women were particularly vulnerable to losing muscle. One in five women with stable body weight lost muscle, while less than one in 10 men did.

“More research is needed to determine whether physical activity offers the best solution to prevent muscle loss or fatty deposits in muscle,” Dr Brown said. “But the findings provide colorectal cancer patients with more incentive to engage in physical activity programs that maintain and build muscle.”

Source: News-Medical.Net