Carbon Chemist

Tag: Muscle

  • Study examines meat consumption’s impact on mortality risk in the frail

    Study examines meat consumption’s impact on mortality risk in the frail

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    Frailty, a clinical syndrome affecting almost 10% of the elderly, undermines their ability to handle stress.

    Nutrition plays a key role in frailty development, with protein supplements often used to boost strength and physical function in frail older adults. Although meat is a rich protein source, its impact on the health of frail individuals remains under-researched.

    A recent study in The Journal of Nutrition, Health and Aging explores how meat consumption influences the risk of death in frail populations.

    Study: Associations between meat consumption and all-cause and cause-specific mortality in middle-aged and older adults with frailty. Image Credit: KucherAV/Shutterstock.comStudy: Associations between meat consumption and all-cause and cause-specific mortality in middle-aged and older adults with frailty. Image Credit: KucherAV/Shutterstock.com

    About frailty

    Frailty arises from diminished physiological capacity due to existing deficiencies across various bodily systems, leading to increased vulnerability to stressors and a higher demand for medical care in the elderly.

    Recent studies aim to enhance the well-being of frail individuals by investigating the roots of frailty and tracking the progression of this condition.

    The role of meat in frailty

    Meat, as a food category, includes red meat, fish, and poultry. Rich in proteins and micronutrients, meat is important for building and maintaining muscle strength, enhancing physical strength, and minimizing the incidence of malnutrition in the elderly.

    Even though frail people need to eat more protein, prior research has demonstrated a positive association of red meat with frailty, unlike other types of protein.

    This could be due to the high saturated fat content in red meat that is associated with increased cardiovascular disease (CVD) risk.

    In addition, processed meat contains nitrites and other preservatives that may trigger oxidative stress and inflammation, both of which cause CVD and metabolic disease.

    Such findings have led to recommendations, both by the World Health Organization (WHO) and many national nutritionist bodies, to eat less red meat and processed meat.

    What did the study show?

    There were around 20,000 participants, with a mean age of 58 years. About 60% were female. About 38% and 12% ate red meat and processed meat, respectively.

    About a fifth consumed poultry. Increased frequency of poultry consumption was associated with a lower risk of death from all causes. Compared to those who had poultry less than once a week, those who had it 1-2 times had a 10% lower risk, while those who ate it >4 times a week had a 33% lower risk.

    Deaths from cancer were also lower, at 10% and 20%, for those who had poultry 1-2 times vs >4 times a week. Moreover, mortality from CVD was reduced by 15%, 25%, and 50%, among those who ate it 1-2, 2-4, and >4 times a week, respectively.

    The opposite trends were seen among those who had higher processed meat consumption. All-cause mortality was increased by 10% and 20% among those who ate processed meat 2-4 vs >4 times a week, respectively.

    Deaths from CVD were higher by 15% and 25% among those who had processed meat 1-4 times vs >4 times a week, respectively.

    There was a U-shaped relationship between red meat intake and mortality. The death rates from all causes, cancer, and CVD were all lower among those who ate red meat up to 2 times a week, but only the first was significant.

    The risk of all-cause deaths was 14% lower in this group compared to those who had red meat less than once a week.

    For each additional 25 g of red meat, the risk of all-cause mortality and deaths from CVD among the frail increased by 7% and 16%, respectively. This was not the case for overall meat consumption.

    If processed meat was replaced by oily fish, like sardines, the risk of all-cause death was 5% lower. If substituted by poultry, it was 9% lower for all-cause deaths and 7% less for cancer deaths. CVD mortality was reduced by 13%.

    If fish replaced red meat, all-cause mortality went down by 3%, but if oily fish was consumed, it went down by 6%. Substitution with cheese led to a 4% reduction but by 10% for poultry.

    These substitutions were also more heart-friendly, with poultry being associated with 13% lower CVD mortality vs 5% for cheese and for fish.

    Interestingly, increased red meat consumption was linked to a higher risk of all-cause mortality among males only.

    This risk was also stronger for processed meat consumption among males and those with a body mass index (BMI) of 25 kg/m3 or higher. BMI was also similarly linked to increased risk for all-cause mortality with increasing meat consumption.

    Lessons to learn

    “We need much more research on optimal dietary components for people with frailty because current clinical guidelines are mainly based on expert consensus because of the lack of an evidence base.”

    These findings from a study that explores the different types of meat consumption in relation to mortality risk in frail individuals supply a significant foundation for such recommendations.

    They corroborate earlier studies showing the adverse impact of processed meat on all-cause and cardiovascular mortality, which outweighs the potential benefit in terms of the protein supplied.

    The association of red meat intake >2 times a week with increased mortality has not been reported by other studies but may be due to the saturated fat content, which may boost the risk of CVD.

    The results indicate that “poultry and fish could be a healthier alternative to red and processed meat among frail individuals.”

    Further research is necessary to explore the interaction of BMI with processed meat consumption and mortality risk. The reasons for increased mortality with red meat intake in males remain unexplained, inviting future studies.

    Journal reference:

    • Jie Chen a, Weihao Xu, Lintao Dan, Junhan Tang b, Jirong Yue e,  Emiel O. Hoogendijk f, and Chenkai Wu (2024). Associations between meat consumption and all-cause and cause-specific mortality in middle-aged and older adults with frailty. The Journal of Nutrition, Health and Aging. doi: http://dx.doi.org/10.1016/j.jnha.2024.100191. 

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  • Sensory neurons play pivotal role in orchestrating tissue repair and regeneration

    Sensory neurons play pivotal role in orchestrating tissue repair and regeneration

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    Researchers from Monash University and Osaka University have unveiled a groundbreaking discovery regarding the pivotal role of sensory neurons in orchestrating tissue repair and regeneration, offering significant promise for patients with poorly healing tissues and diabetes.

    Collaborating with Professor Shizuo Akira from IFReC, a research team led by Associate Professor Mikaël Martino from Monash University, who also held a cross-appointment position at Osaka University, recently published a significant advancement in regenerative medicine in Nature.

    Their research sheds light on the intricate interplay between the nervous and immune systems, highlighting the critical involvement of sensory neurons in the repair and regeneration of tissues. While nociceptive sensory neurons are primarily associated with pain sensation, their contribution to tissue regeneration has been unclear until now. Through their research, the team demonstrated that the removal of a specific subtype of sensory neurons containing the Nav1.8 ion channel significantly impairs skin wound repair and muscle regeneration following injury. Furthermore, they revealed that the endings of these sensory neurons extend into injured skin and muscle tissues, communicating with immune cells through the neuropeptide calcitonin gene-related peptide (CGRP) during the healing process. This neuropeptide plays a crucial role in influencing immune cells to aid tissue healing after injury. In preclinical models, such as mice lacking sensory neurons and diabetic mice with damaged peripheral nerve cells, the administration of an engineered version of CGRP, designed to enhance its efficacy, accelerated wound healing and promoted muscle regeneration.

    These findings hold great promise for regenerative medicine, particularly in addressing poorly healing tissues commonly observed in conditions such as diabetes. Looking ahead, the team aims to develop innovative therapies targeting the underlying causes of impaired tissue repair by harnessing neuro-immune interactions.

    Monash University is one of Osaka University’s Global Knowledge Partners, a strategic partnership aimed at developing high-quality and sustainable research and education programs that can contribute to the resolution of global issues. Lead author Mikaël Martino, a key advocate for collaboration between the two universities, emphasized the importance of the strong inter-institutional relationship and cross-appointment system in enabling international researchers like himself to collaborate effectively with scientists at Osaka University.

    Source:

    Journal reference:

    Lu, Y.-Z., et al. (2024). CGRP sensory neurons promote tissue healing via neutrophils and macrophages. Nature. doi.org/10.1038/s41586-024-07237-y.

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  • Study reveals trigonelline as a therapeutic agent for mitochondrial dysfunction in aging

    Study reveals trigonelline as a therapeutic agent for mitochondrial dysfunction in aging

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    A recent study published in the journal Nature Metabolism reported that low levels of nicotinamide adenine dinucleotide (NAD+) and mitochondrial dysfunction observed in sarcopenia and during the aging of skeletal muscles were functionally linked to serum levels of trigonelline, a natural alkaloid.

    Study: Trigonelline is an NAD+ precursor that improves muscle function during ageing and is reduced in human sarcopenia. Image Credit: BigBlueStudio/Shutterstock.comStudy: Trigonelline is an NAD+ precursor that improves muscle function during ageing and is reduced in human sarcopenia. Image Credit: BigBlueStudio/Shutterstock.com

    Background

    Sarcopenia is the age-related decline in skeletal muscle due to the wasting of myofiber, resulting in impaired contraction of muscle fibers, decreased mobility, and disability.

    The clinical manifestations of sarcopenia include reduced muscle mass, and, consequently, decreased gait speed and strength. Studies have found that mitochondrial dysfunction plays a significant role in the development of sarcopenia.

    Phenotypes of muscle aging are driven by factors such as lower mitochondrial biogenesis, decreased cellular respiration and adenosine triphosphate (ATP) production, and changes in mitochondrial dynamics.

    Recent research has been focused on understanding the role of systemic factors such as pro-inflammatory cytokines, circulating anabolic amino acids, and fluctuations in lipid, vitamin, and glucose metabolism in influencing mitochondrial function and impacting muscle strength.

    Low levels of NAD+ have been identified recently as being one of the hallmarks of muscle aging and sarcopenia, along with mitochondrial dysfunction.

    However, whether decreasing levels of NAD+ are linked to circulating molecular markers that can be used as clinical biomarkers remains unknown.

    About the study

    In the present study, the researchers investigated whether individuals with sarcopenia had varying serum levels of vitamin B or kynurenine metabolome as compared to healthy individuals to determine systemic changes linked to NAD+ metabolism alterations and mitochondrial dysfunction.

    NAD+ is derived from vitamin B3 precursors and is an essential cofactor for organismal and cellular metabolism.

    In mammals, NAD+ can be produced from dietary precursors such as nicotinamide mononucleotide and nicotinamide riboside through the nicotinamide riboside kinase pathway, nicotinic acid or niacin through the nicotinate phosphoribosyltransferase-dependent Preiss–Handler pathway, and from tryptophan and nicotinamide.

    Rodent studies have also corroborated the findings from human studies that aging skeletal muscles show declining NAD+ levels.

    The present study included participants above the age of 60 who had sarcopenia and an equal number of age-matched, healthy controls. Muscle biopsy samples were collected for analysis from all participants. A digital dynamometer was used to measure grip strength, while dual-energy X-ray absorptiometry was used to measure the appendicular lean mass index.

    A 24-hour recall method was employed to assess the dietary intake, and household portions of all reported foods and beverages were converted to grams using standard references.

    Ribonucleic acid (RNA) sequencing was performed using the vastus lateralis muscle biopsies, and the genetic dataset obtained was used for pathway analysis.

    Additionally, the concentration of NAD+ from tissue samples was quantified enzymatically, and liquid chromatography-mass spectrometry was used for the high-resolution analysis of the NAD+ metabolomes in the in vivo samples and cells.

    A wide range of cellular assays were performed to assess cell death, mitochondrial function, knockdown of nicotinate phosphoribosyltransferase gene, G-protein coupled receptor agonism, and stability of the NAD+ precursor.

    Muscle tissues from the biopsies were also stained for histological assessments to observe muscle architecture.

    The nicotinate phosphoribosyltransferase knockdown studies were performed using rodent models, and RNA extracts from the rodent tissue were used for quantitative polymerase chain reaction (qPCR) and immunoblot assays.

    Results

    The results showed that although the vitamin B3 metabolites or any of the other metabolites analyzed in the study showed no alterations linked to sarcopenia, the individuals with sarcopenia had low levels of trigonelline, a natural alkaloid produced by mammals and plants.

    The appendicular lean mass index, as well as gait speed and grip strength measurements, showed a correlation between muscle mass and levels of trigonelline. Additionally, serum trigonelline levels were found to be linked to the levels of NAD+ in the skeletal muscles.

    The pathway enrichment studies from the rodent tissues also indicated that numerous signaling and metabolic pathways, such as the mitochondrial oxidative phosphorylation pathway, were positively associated with serum trigonelline levels.

    The dietary intake analysis found that caffeine consumption was not associated with changes in trigonelline levels in the serum. Still, it indicated that fiber and folate intake could influence the circulating levels of trigonelline.

    Changes in vitamin B3 intake also did not seem to influence the association between muscle strength and trigonelline levels. These findings suggested that trigonelline was a new metabolite that could be used as a biomarker to assess NAD+ levels, mitochondrial metabolism, and muscle strength.

    Conclusions

    To summarize, the study investigated the association between the levels of vitamin B3 metabolome and NAD+ levels, muscle mass, and mitochondrial dysfunction related to sarcopenia through RNA sequencing, histological analyses, animal studies, and numerous assays.

    While the results showed no associations between the hallmarks of sarcopenia and the vitamin B3 metabolome, low levels of trigonelline, a natural alkaloid found in humans, were found to be associated with a decrease in NAD+ levels, muscle mass decline, and mitochondrial dysfunction.

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  • Natural molecule trigonelline can help to improve muscle health and function

    Natural molecule trigonelline can help to improve muscle health and function

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    A research consortium led by Nestlé Research in Switzerland and the Yong Loo Lin School of Medicine, National University of Singapore (NUS Medicine) made a recent discovery that the natural molecule trigonelline present in coffee, fenugreek, and also in the human body, can help to improve muscle health and function. In an international collaboration among the University of Southampton, University of Melbourne, University of Tehran, University of South Alabama, University of Toyama and University of Copenhagen, the work builds on a previous collaborative study that described novel mechanisms of human sarcopenia.

    Sarcopenia is a condition where cellular changes that happen during aging gradually weaken the muscles in the body and lead to accelerated loss of muscle mass, strength and reduced physical independence.

    One important problem during sarcopenia is that the cellular cofactor NAD+ declines during ageing, while mitochondria, the energy powerhouses in our cells, produce less energy. The study team discovered that levels of trigonelline were lower in older people with sarcopenia. Providing this molecule in pre-clinical models resulted in increased levels of NAD+, increased mitochondrial activity and contributed to the maintenance of muscle function during aging.

    NAD+ levels can be enhanced with different dietary precursors like the essential amino acid L-tryptophan (L-Trp), and vitamin B3 forms such as nicotinic acid (NA), nicotinamide (NAM), nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN).

    Assistant Professor Vincenzo Sorrentino from the Healthy Longevity Translational Research Programme at NUS Medicine added, “Our findings expand the current understanding of NAD+ metabolism with the discovery of trigonelline as a novel NAD+ precursor and increase the potential of establishing interventions with NAD+-producing vitamins for both healthy longevity and age-associated diseases applications”.

    Nutrition and physical activity are important lifestyle recommendations to maintain healthy muscles during aging.

    We were excited to discover through collaborative research that a natural molecule from food cross-talks with cellular hallmarks of aging. The benefits of trigonelline on cellular metabolism and muscle health during aging opens promising translational applications.”

    Jerome Feige, Head of the Physical Health department at Nestlé Research

    Source:

    National University of Singapore, Yong Loo Lin School of Medicine

    Journal reference:

    Membrez, M., et al. (2024). Trigonelline is an NAD+ precursor that improves muscle function during ageing and is reduced in human sarcopenia. Nature Metabolism. doi.org/10.1038/s42255-024-00997-x.

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  • Bioengineering edible mycelium to enhance nutritional value, color, and flavor

    Bioengineering edible mycelium to enhance nutritional value, color, and flavor

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    In a recent study published in Nature Communications, researchers developed a modular synthetic biology toolkit for Aspergillus oryzae, an edible fungus used in fermented foods, protein production, and meat alternatives.

    Study: Edible mycelium bioengineered for enhanced nutritional value and sensory appeal using a modular synthetic biology toolkit. Image Credit: Rattiya Thongdumhyu/Shutterstock.comStudy: Edible mycelium bioengineered for enhanced nutritional value and sensory appeal using a modular synthetic biology toolkit. Image Credit: Rattiya Thongdumhyu/Shutterstock.com

    Background

    Food production is estimated to account for a third of greenhouse gas emissions worldwide, contributing to biodiversity loss, environmental degradation, and new diseases.

    Transitioning from industrial animal agriculture to alternatives is necessary to mitigate the planetary impact and sustainably feed the global population. Microbial food production offers improved safety and efficiency, more precise production control, and reduced animal suffering.

    Filamentous fungi are a diverse group of microbes, including mushrooms and molds, and are highly advantageous for microbial food production.

    Besides, their naturally high secretion capacity makes them potent hosts for protein production. In addition, owing to its filamentous structure that mimics the animal muscle structure, fungal biomass (mycelia) can be formulated into alternatives to meat (mycoprotein).

    The study and findings

    In the present study, researchers developed a modular synthetic biology toolkit for A. oryzae, a safe and edible fungus with a history of palatable consumption.

    They created an alternative, easy-to-use clustered, regularly interspersed short palindromic repeats (CRISPR)–CRISPR-associated protein 9 (Cas9) approach, compatible with existing reagents.

    This approach involved transforming CRISPR-Cas9 ribonucleoprotein complexes directly instead of encoding single-guide RNAs (sgRNAs) and Cas9 from a plasmid.

    Moreover, the DNA template used to fix double-strand breaks contained an orotidine-5′-phosphate decarboxylase gene (pyrG) marker for positive and negative selection.

    The system was designed such that a successful loop out of pyrG could only occur upon integrating the fixing template at the site of interest, wherein identical 300 bp sequences will flank it.

    Ectopic integrations due to non-homologous end joining (NHEJ) in this system cannot loop out or survive on media with 5-fluoroorotic acid. A vital feature of this design was the recyclability of the pyrG marker upon insertion at the correct locus.

    Further, candidate-neutral loci in A. oryzae were investigated to integrate genes for overexpression. The researchers explored the intergenic regions in the A. oryzae RIB40 genome and ranked the expression of two genes surrounding them.

    A list of candidate loci predicted for high gene expression was generated, and ten regions were selected for further analysis.

    Next, the team integrated green fluorescent protein (GFP) cassettes under the control of a strong, constitutive promoter (pTEF1) and examined fluorescence on the conidia of looped-out strains.

    Of the ten loci, nine exhibited highly efficient integration, and GFP expression was detected from eight of these. All loci demonstrated higher expression than the positive control.

    Next, the researchers aimed to establish a synthetic expression system (SES) in A. oryzae. To this end, they evaluated the ability of a characterized synthetic transcription factor (sTF) to drive the expression of mCherry from a core promoter (Cp).

    They genetically integrated the sTF and induced a low basal expression under a Cp from A. niger. Separately, an mCherry cassette with 6x upstream activating sequences (UAS) was integrated at a different genomic location upstream of the Cp.

    The team observed mCherry expression in conidia and mycelia. Both the sTF and UAS were required for the activity. Next, the team aimed to bioengineer an edible mycelium, focusing on the bioactive amino acid ergothioneine.

    They speculated that its production could be increased by modulating the expression of endogenous ergothioneine biosynthetic genes in A. oryzae.

    Orthologs of Egt1 and Egt2, enzymes from Neurospora crassa implicated in ergothioneine biosynthesis, were identified in A. oryzae.

    The orthologs were then inserted at neutral loci; both genes were expressed under a bidirectional promoter or separately at different locations. Ergothioneine levels in the mycelium were low in RIB40, the background strain.

    However, its levels were 11- and 21-fold elevated in bidirectional and separate promoter strains compared to RIB40. Ergothioneine levels in the bidirectional promoter stain were similar to those in oyster mushrooms. By contrast, its levels were 1.5-fold higher in the separate promoter strain.

    There were no differences in protein content between engineered and wild-type strains. Nevertheless, a slight growth defect was observed with ergothioneine overproduction.

    Next, the researchers applied these tools to enhance the sensory properties of the edible biomass. They targeted heme biosynthesis, as heme gives meat its (red) color and flavor upon cooking.

    They identified potential heme biosynthetic genes in A. oryzae and targeted the expression of five predicted rate-limiting enzymes. Additionally, two copies of soy leghemoglobin were expressed as a potential heme sink, as high levels of free heme could be cytotoxic.

    The biomass of the engineered strain was four-fold higher than that of the non-engineered strain.

    Upon harvesting, the biomass was red compared to off-white in RIB40. This color difference persisted after cooking, enhancing the meat-like appearance of the fungal biomass.

    The engineered mycoprotein contained all essential amino acids. Protein content or growth yield was not lower in the engineered strain.

    Conclusions

    The researchers developed a synthetic toolkit to integrate and regulate genes and pathways. They leveraged this toolkit and engineered A. oryzae mycoprotein to (over)produce ergothioneine at levels far greater than in natural dietary sources, i.e., mushrooms.

    Additionally, the mycelia were engineered to overproduce heme for enhanced color and flavor. Notably, this work represents an early prototype; further evaluations of sensory attributes, food safety, consumer acceptance, and regulatory landscape are required.

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  • Lactate’s role in driving cancer cachexia uncovered

    Lactate’s role in driving cancer cachexia uncovered

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    A recent Nature Metabolism study reports that circulating lactate levels are positively associated with weight loss in cancer cachexia patients. Mouse model experiments also revealed that adipose-specific G-protein-coupled receptor 81 (GPR81) is a key mediator of the catabolic effects of lactate. 

    Study: Activation of GPR81 by lactate drives tumor-induced cachexia. Image Credit: Pixel-Shot / Shutterstock.com Study: Activation of GPR81 by lactate drives tumor-induced cachexia. Image Credit: Pixel-Shot / Shutterstock.com

    What is cachexia?

    Cachexia is a complicated metabolic syndrome that is associated with rapid body weight loss, including loss of fat and muscle mass.

    Patients with cancer cachexia often develop anemia, fatigue, asthenia, and anorexia, which deteriorate their quality of life and reduce their tolerance to cancer therapies. As a result, cachexia accounts for around 20% of patients with cancer-related deaths.

    To date, the precise mechanism responsible for the development of cancer cachexia is not well understood. Previous studies have shown that inflammatory cytokines, such as interleukin 6 (IL-6), tumor necrosis factor (TNF), interferon γ (IFN-γ), and transforming growth factor-β, induce the remodeling of adipose and muscle due to accelerated growth of cancer cells, all of which contribute to the pathogenesis of cancer cachexia.

    Anti-inflammation treatments have not been associated with positive effects in alleviating cancer cachexia. Therefore, more research is needed to better understand the association between tumor manifestations and poor host metabolism.

    About the study

    The current study focuses on causally identifying the connecting factors between tumors and extensive catabolism in cancer cachexia. To determine serum lactate levels, samples collected from lung adenocarcinoma patients were used to calibrate the Biosen C-Line glucose lactate analyzer.

    The systemic metabolic changes associated with cachexia were profiled using a mouse xenograft model of Lewis lung cancer (LLC) cells. Mice with tumor burden exhibited significant weight loss with reduced white adipose tissue (WAT). 

    Study findings

    Metabolomics screening of a mouse model of cancer cachexia identified lactate as the top differential metabolite. The identity of this metabolite was corroborated by the peak in the mass spectrum, which was compared to the standard. 

    Lactate levels were strongly correlated with reduced body weight, particularly among patients with lung adenocarcinoma with cancer cachexia. Higher circulating and adipose interstitial lactate levels were observed before body weight loss. Additionally, the wasting phenotype lactate infusion results were similar to those induced by the tumor.

    An osmotic minipump-mediated lactate infusion led to a persistent average increase of circulating lactate without a change in blood pH; however, d-lactate exhibited did not appear to influence weight loss. The sustained high lactate levels in many cancer patients were negatively associated with their prognosis. 

    Adipose GPR81 was identified as the primary mediator of lactate’s pro-catabolic effects. More specifically, GPR81 deficiency was found to block lactate infusion- and tumor-triggered cachectic manifestations, thus establishing lactate/GPR81 as the key connection between metabolic reprogramming in cancer cachexia and tumors.

    The catabolic remodeling of WAT has also been identified as an early pathological event in cancer cachexia. In mouse models, depletion of key enzymes in lipolysis alleviated cachectic phenotypes, thereby confirming the crucial role of adipose tissue wasting in cancer cachexia.

    A lactate-stimulated cachectic pathway activated the GPR81-Gαi/o-Gβγ-RhoA/ROCK1-p38 signaling cascade, not accompanied by the upregulation of parathyroid hormone-related protein (PTHrP). To trigger WAT browning and lipolysis, chronic elevation of blood lactate is sufficient.

    Additionally, phosphoproteomics data showed the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) in the GPR81−/− iWAT. This activation of ERK1/2 in GPR81-deficient mice could influence persistent adipogenesis, thereby muting lactate- and tumor-induced adipose wasting. 

    Conclusions

    The current study identified host GPR81 as the key mediator of cancer cachexia, with lactate activating GPR81 to ultimately support tumor growth. This observation aligns with previous studies reporting the inhibition of GPR81 expression suppressing the growth of pancreatic and breast cancer cells. The experimental findings strongly suggest that the palliation of cachectic symptoms in GPR81−/− is mediated through GPR81 deficiency in the host.

    Both in vitro and in vivo experiments associated with tumor growth revealed that the lack of GPR81 expression in LLC cells repressed cancer proliferation. Thus, lactate/GPR81 contributes to both cancer progression and cachexia, which deteriorates disease outcomes.

    Mechanistically, lactate activates GPR81, which induces adipose metabolic remodeling through Gαi/o-Gβγ–RhoA/ROCK1–p38 signaling cascade. This leads to muscle dystrophy and systemic hypercatabolism.

    Taken together, the study findings indicate that GPR81 could be targeted and blocked to alleviate metabolic impairments involved in cancer cachexia.

    Journal reference:

    • Liu, X., Li, S., Cui, Q., et al. (2024) Activation of GPR81 by lactate drives tumor-induced cachexia. Nature Metabolism. doi:10.1038/s42255-024-01011-0

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  • Common cranberry can help improve performance of competitive athletes

    Common cranberry can help improve performance of competitive athletes

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    Competitive athletes are always looking for an extra edge that can help them improve performance. According to a new study by Concordia researchers published in the journal Physical Activity and Nutrition, they can find one in the common cranberry.

    In a series of trials involving trained distance runners, the researchers found that ingesting a cranberry supplement for 28 consecutive days led to noticeable improvements in both performance and muscle fatigue following 1,500-metre time trials. Reoxygenation rates were faster and running speeds improved by 1.5 per cent.

    When it comes to elite athletes, any advantage can make the difference between finishing fifth or on the podium.”


    Andreas Bergdahl, Associate Professor in the Department of Health, Kinesiology and Applied Physiology and the paper’s senior author

    Effects of different energy systems

    The researchers recruited 14 high-level runners from Concordia’s varsity track and field team and from two Montreal running clubs, who are performing at least five hours of endurance training a week.

    The athletes ran two time trials over three separate visits, one a 1,500-metre, the other a 400-metre. The first visit was used as a baseline. At the second, they were given a single large dose of cranberry extract two hours before running. The athletes were then instructed to consume a small dose of cranberry extract daily for 28 days, after which they repeated the runs for a third time.

    “We selected these distances to test the effects the cranberry extract had on different energy systems,” says Francis Parenteau, a PhD candidate and the paper’s lead author. “The 400-metre is shorter and of higher intensity and involves the anaerobic system. The 1,500-metre uses the aerobic system but is shorter than what the athletes usually run. Since they do not train to run that distance, we were able to isolate training effects as a variable.”

    Besides their running time, the researchers measured their post-exercise blood lactate, a marker for potential muscle fatigue and lack of oxygen. They also attached a portable near-infrared spectroscopy device to the runners to measure muscle oxygenation levels before, during and after their runs.

    Following data analysis, the researchers found that 28 days of cranberry extract consumption demonstrated a trend toward increased speed in the 1,500-metre time trial but not in the 400-metre. However, they did notice that lactate buildup was reduced following the 400-metre but not the 1,500-metre compared to baseline.

    The data also indicated that the cranberry extract promoted better oxygen extraction by the muscle, improved lactate clearance and slower muscle deoxygenation.

    A runner’s best friend, made in Quebec

    Cranberries are extraordinarily rich in polyphenols, a natural compound with antioxidant properties. These characteristics help protect the body from the harmful effects of free radical molecules produced by strenuous exercise.

    Cranberries are also indigenous to and a major industrial crop for Quebec. The province produces roughly 60 per cent of Canada’s cranberry yield, according to Statistics Canada.

    “The beauty of this is that it is all natural,” says Bergdahl. “It is an ergogenic aid, meaning that it is performance-enhancing, but it is not an anabolic steroid. Athletes can get this important boost in their performance just by consuming more cranberries.”

    Source:

    Journal reference:

    Parenteau, F., et al. (2023). Cranberry supplementation improves physiological markers of performance in trained runners. Physical Activity and Nutrition. doi.org/10.20463/pan.2023.0032.

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  • A call for targeted research and therapies

    A call for targeted research and therapies

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    In a recent review published in the journal Cell Metabolism, researchers elucidated mechanisms and evaluated therapies for impaired skeletal muscle regeneration in diabetes, identifying research gaps and future directions.

    Study: Impaired skeletal muscle regeneration in diabetes: From cellular and molecular mechanisms to novel treatments. Image Credit: Crevis / ShutterstockStudy: Impaired skeletal muscle regeneration in diabetes: From cellular and molecular mechanisms to novel treatments. Image Credit: Crevis / Shutterstock

    Background 

    Diabetes, a growing public health issue, continues to surge despite extensive research and healthcare efforts. It leads to various forms of diabetic myopathy, irrespective of its type, causing a decline in skeletal muscle mass and function. This decline not only worsens obesity and hyperglycemia but also affects locomotion, energy metabolism, and glucose regulation, further deteriorating muscle structure and function. Additionally, diabetes impairs muscle regeneration, potentially worsening conditions like ischemia and foot ulcers by promoting fibrosis and hindering myofiber recovery. Further research is needed to better understand and develop targeted interventions for the complex mechanisms underlying impaired muscle regeneration in diabetes.

    Skeletal muscle abnormalities in diabetes

    Diabetes, alongside its comorbidities like obesity, hypertension, and dyslipidemia, significantly affects skeletal muscle structure, function, and metabolism. The complex nature of diabetes complicates the identification of effective therapeutic targets. Other contributing factors include aging, inactivity, and poor nutrition. Key observed abnormalities in diabetic patients include reduced muscle mass and strength, abnormal lipid deposition, fiber atrophy, and altered myokine secretion, contributing to decreased functional capacity and quality of life.

    Diabetes not only leads to muscle degeneration but also impairs the muscle’s ability to regenerate, complicating injuries such as ischemia and foot ulcers. The regeneration process, involving both muscle stem cells (MuSCs) and non-MuSCs, is hampered, as indicated by excessive fibrosis and delayed myofiber maturation.

    Skeletal muscle regeneration in diabetes Diabetes and its associated complications, including obesity and hyperglycemia, impact multiple cell populations (MuSCs, neutrophils, macrophages, T cells, FAPs, and mast cells) that play a vital role in the process of muscle regeneration (i.e., degeneration and inflammation, regeneration, and maturation and functional recovery).

    Skeletal muscle regeneration in diabetes Diabetes and its associated complications, including obesity and hyperglycemia, impact multiple cell populations (MuSCs, neutrophils, macrophages, T cells, FAPs, and mast cells) that play a vital role in the process of muscle regeneration (i.e., degeneration and inflammation, regeneration, and maturation and functional recovery).

    Degeneration and inflammation

    Muscle injuries trigger necrosis and inflammation, marked by fiber breakdown and protein leakage into the serum. The process, essential for tissue repair, draws in immune cells like neutrophils and macrophages. Diabetes compounds this degeneration, amplifying damage, and hampering regeneration, highlighting the metabolic impact on muscle recovery.

    Regeneration process

    Diabetes negatively impacts the muscle regeneration process, notably affecting the activation, proliferation, and differentiation of MuSCs and the roles of fibro-adipogenic progenitors (FAPs). Treatments like metformin offer some hope by potentially modifying FAP activity. However, delayed regeneration in diabetic models underlines the urgent need for deeper insights into how diabetes disrupts muscle repair mechanisms.

    Challenges in muscle recovery

    Efficient muscle regeneration requires not only the formation of new myofibers but also the reconstitution of the extracellular matrix, vascular network, and innervation. Diabetes and obesity complicate this process, showing delayed functional recovery, increased collagen accumulation, and impaired neuromuscular junction adaptations.

    Diabetic impacts on muscle fiber and insulin signaling

    Diabetes shifts muscle fiber composition towards type II fibers, which are more prone to damage and impair regeneration. Insulin resistance disrupts muscle cell growth pathways, while hyperinsulinemia and lipotoxicity inhibit crucial recovery processes like autophagy and protein metabolism. These changes suggest that targeting fiber-type transitions and improving insulin signaling could enhance muscle regeneration in diabetes.

    Diabetic challenges in muscle regeneration signaling

    Diabetes triggers elevated pro-inflammatory cytokines and oxidative stress, disrupting muscle repair by inhibiting growth pathways and promoting protein breakdown. Concurrently, increased myostatin levels and NOTCH and WNT signaling alterations impair muscle cell proliferation and differentiation. Moreover, the compromised Adenosine Monophosphate-Activated Protein Kinase (AMPK) signaling pathway further hinders MuSC function and regeneration, highlighting complex challenges in diabetic muscle repair.

    Disentangling diabetes and comorbidity effects on muscle regeneration

    Diabetes significantly impairs muscle regeneration, but pinpointing whether diabetes itself or related comorbidities such as obesity and sarcopenia are responsible remains challenging. Muscle health is influenced by a number of factors, including genetics, diet, and physical activity, complicating the isolation of diabetes’ direct effects. Studies often struggle to establish control groups that adequately account for these variables, leading to ambiguity about the specific impacts of diabetes versus other conditions. For instance, research using obese diabetic mice versus lean controls has difficulty distinguishing whether observed effects are due to obesity or diabetes itself. 

    Challenges in research models and therapeutic approaches

    There is no definitive animal model for studying diabetes’ impact on muscle regeneration, complicating the translation of findings to humans. Treatments for muscle regeneration in diabetes are varied, spanning from exercise and dietary supplements to advanced cell therapies, yet their effectiveness often falls short in addressing muscle fibrosis. Despite the promise shown by certain therapies in improving muscle health in diabetes, rigorous clinical trials are needed to assess their true efficacy in muscle regeneration, specifically within diabetic populations.

    Future directions in muscle regeneration research

    Addressing these gaps requires a multifaceted approach. Research must refine its models and control groups to isolate the effects of diabetes from those of comorbidities and lifestyle factors. Advanced genetic and omics technologies offer new avenues to uncover the intricate mechanisms at play in diabetic muscle regeneration. Furthermore, integrating therapies such as exercise, dietary interventions, and possibly cell therapies may hold the key to enhancing muscle repair in diabetic patients. However, more research is essential to navigate the complexities of muscle regeneration in diabetes and develop effective treatments.

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  • Soft, stretchy throat patch empowers speech in people with voice disorders

    Soft, stretchy throat patch empowers speech in people with voice disorders

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    People with voice disorders, including those with pathological vocal cord conditions or who are recovering from laryngeal cancer surgeries, can often find it difficult or impossible to speak. That may soon change.

    A team of UCLA engineers has invented a soft, thin, stretchy device measuring just over 1 square inch that can be attached to the skin outside the throat to help people with dysfunctional vocal cords regain their voice function. Their advance is detailed this week in the journal Nature Communications.

    The new bioelectric system, developed by Jun Chen, an assistant professor of bioengineering at the UCLA Samueli School of Engineering, and his colleagues, is able to detect movement in a person’s larynx muscles and translate those signals into audible speech with the assistance of machine-learning technology -; with nearly 95% accuracy.

    The breakthrough is the latest in Chen’s efforts to help those with disabilities. His team previously developed a wearable glove capable of translating American Sign Language into English speech in real time to help users of ASL communicate with those who don’t know how to sign.

    The tiny new patch-like device is made up of two components. One, a self-powered sensing component, detects and converts signals generated by muscle movements into high-fidelity, analyzable electrical signals; these electrical signals are then translated into speech signals using a machine-learning algorithm. The other, an actuation component, turns those speech signals into the desired voice expression.

    The two components each contain two layers: a layer of biocompatible silicone compound polydimethylsiloxane, or PDMS, with elastic properties, and a magnetic induction layer made of copper induction coils. Sandwiched between the two components is a fifth layer containing PDMS mixed with micromagnets, which generates a magnetic field.

    Utilizing a soft magnetoelastic sensing mechanism developed by Chen’s team in 2021, the device is capable of detecting changes in the magnetic field when it is altered as a result of mechanical forces -; in this case, the movement of laryngeal muscles. The embedded serpentine induction coils in the magnetoelastic layers help generate high-fidelity electrical signals for sensing purposes.

    Measuring 1.2 inches on each side, the device weighs about 7 grams and is just 0.06 inch thick. With double-sided biocompatible tape, it can easily adhere to an individual’s throat near the location of the vocal cords and can be reused by reapplying tape as needed.

    Voice disorders are prevalent across all ages and demographic groups; research has shown that nearly 30% of people will experience at least one such disorder in their lifetime. Yet with therapeutic approaches, such as surgical interventions and voice therapy, voice recovery can stretch from three months to a year, with some invasive techniques requiring a significant period of mandatory postoperative voice rest.

    “Existing solutions such as handheld electro-larynx devices and tracheoesophageal- puncture procedures can be inconvenient, invasive or uncomfortable,” said Chen who leads the Wearable Bioelectronics Research Group at UCLA, and has been named one the world’s most highly cited researchers five years in a row. “This new device presents a wearable, non-invasive option capable of assisting patients in communicating during the period before treatment and during the post-treatment recovery period for voice disorders.”

    How machine learning enables the wearable tech

    In their experiments, the researchers tested the wearable technology on eight healthy adults. They collected data on laryngeal muscle movement and used a machine-learning algorithm to correlate the resulting signals to certain words. They then selected a corresponding output voice signal through the device’s actuation component.

    The research team demonstrated the system’s accuracy by having the participants pronounce five sentences -; both aloud and voicelessly -; including “Hi, Rachel, how are you doing today?” and “I love you!”

    The overall prediction accuracy of the model was 94.68%, with the participants’ voice signal amplified by the actuation component, demonstrating that the sensing mechanism recognized their laryngeal movement signal and matched the corresponding sentence the participants wished to say.

    Going forward, the research team plans to continue enlarging the vocabulary of the device through machine learning and to test it in people with speech disorders.

    Other authors of the paper are UCLA Samueli graduate students Ziyuan Che, Chrystal Duan, Xiao Wan, Jing Xu and Tianqi Zheng -; all members of Chen’s lab.

    The research was funded by the National Institutes of Health, the U.S. Office of Naval Research, the American Heart Association, Brain & Behavior Research Foundation, the UCLA Clinical and Translational Science Institute, and the UCLA Samueli School of Engineering.

    Source:

    University of California – Los Angeles

    Journal reference:

    Che, Z., et al. (2024). Speaking without vocal folds using a machine-learning-assisted wearable sensing-actuation system. Nature Communications. doi.org/10.1038/s41467-024-45915-7.

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  • Microfluidic chips advance neurodegenerative disease research

    Microfluidic chips advance neurodegenerative disease research

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    A review article published in the journal Nature Communications provides a detailed overview of recent developments in microfluidic chip models for neurodegenerative diseases.

    Study: Neuropathogenesis-on-chips for neurodegenerative diseases. Image Credit: luchschenF / ShutterstockStudy: Neuropathogenesis-on-chips for neurodegenerative diseases. Image Credit: luchschenF / Shutterstock

    Background

    Recent advancements in medical science have significantly increased human life expectancy, leading to a gradual risNeuropathogenesis-on-chips for neurodegenerative diseasesNeuropathogenesis-on-chips for neurodegenerative diseases in the aging population globally. This is accompanied by a concomitant increase in the prevalence of age-related neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis.

    Neurodegenerative diseases primarily affect the cognitive and behavioral abilities of older adults. With the accumulation of dysfunctional proteins as the primary initiating factor, these diseases share some common pathogenic characteristics, including specific neuronal loss, gliosis, neuroinflammation, oxidative stress, mitochondrial dysfunction, and early vascular damage.

    Despite advancements in medical science, the development of diagnostic and therapeutic interventions for neurodegenerative diseases remains a challenging task because of the complex multifactorial pathogenesis that progresses gradually.

    Microfluidic organs or organoids-on-chips have provided a unique opportunity to experimentally reproduce critical elements of distinct brain regions associated with neurodegenerative diseases. These miniaturized systems can be used for studying disease pathogenesis, drug development, drug screening, and primary biomedical research purposes.

    Microfluidic chip design  

    The ‘Campenot chamber,’ a compartmentalized in vitro system, was the first microfluidic chip application for brain research. With two fluidically separated chambers, this device is used to study the effects of nerve growth factors on axonal growth. Later, scientists invented several miniaturized systems of neuron-glia cells, the blood-brain barrier, and the neurovascular unit.

    Microfluidic chips typically contain two or more fluidically separated chambers that are connected by microchannels, porous membranes, or phase guides. These connections are required to maintain direct or indirect interactions between homogeneous or heterogeneous cell populations kept in these chambers.      

    The earliest microfluidic chip for the brain was designed by separating a neuronal soma from its neurites using microchannels. This design was used to study directional neurite growth. More advanced neural circuit models were developed later by incorporating multiple chambers for neuronal subpopulations.

    AD is characterized by the inclusion of misfolded amyloid-β (Aβ) and neurofibrillary tangles in pyramidal neurons, primarily in the hippocampus and cortex regions of the brain. b PD is characterized by Lewy body aggregates composed of misfolded α-synuclein and degeneration of dopaminergic neurons in the substantia nigra region of the brain. c ALS is characterized by including mutant TAR DNA-binding protein 43 (TDP-43) and other proteins, degeneration of motor neurons in the motor cortex and spinal cord, and muscle atrophy with dysfunctional proteins. d HD is characterized by including mutant Huntingtin protein (mHTT) and degeneration of medium spiny neurons in the basal ganglia, and corpus striatum of the brain. AD Alzheimer’s disease, ALS amyotrophic lateral sclerosis, BDNF brain-derived neurotrophic factor, EAL endosomal-autophagic-lysosomal pathway, GABA gamma-aminobutyric acid, HD Huntington’s disease, PSEN presenilin 1, SNCA synuclein alpha.AD is characterized by the inclusion of misfolded amyloid-β (Aβ) and neurofibrillary tangles in pyramidal neurons, primarily in the hippocampus and cortex regions of the brain. b PD is characterized by Lewy body aggregates composed of misfolded α-synuclein and degeneration of dopaminergic neurons in the substantia nigra region of the brain. c ALS is characterized by including mutant TAR DNA-binding protein 43 (TDP-43) and other proteins, degeneration of motor neurons in the motor cortex and spinal cord, and muscle atrophy with dysfunctional proteins. d HD is characterized by including mutant Huntingtin protein (mHTT) and degeneration of medium spiny neurons in the basal ganglia, and corpus striatum of the brain. AD Alzheimer’s disease, ALS amyotrophic lateral sclerosis, BDNF brain-derived neurotrophic factor, EAL endosomal-autophagic-lysosomal pathway, GABA gamma-aminobutyric acid, HD Huntington’s disease, PSEN presenilin 1, SNCA synuclein alpha.

    Current neuronal chips contain multiple chambers of different diameters positioned in various geometries. These models also include microchannels with patterned shapes and controlled fluid flow. These features allow for indirect and direct, asymmetric, and symmetric neuronal connections.     

    Extra pump systems and passive hydrostatic pressure can be incorporated into chips to control fluid flow. This helps create disease models by allowing a gradient of chemicals with varying concentrations throughout the cell compartments.  

    Porous membranes with different pore sizes, numbers, and positions can be used on chips as an interface between chambers to enable indirect interactions mediated by soluble chemicals and direct physical contact. This design has been used for mimicking the blood-brain barrier on chips.

    Application of microfluidic chips for neurodegenerative disease pathogenesis

    Microfluidic chips can be used for replicating several anatomical and physiological systems, including the neuromuscular junction, corticostriatal pathway, substantia nigra, blood-brain barrier, glymphatic system, neurovascular unit, and gut-brain axis.

    To provide mechanical, structural, and biochemical cues to cells, 3D extracellular matrix gel has been introduced on chips, which allows for studying cell morphology, migration patterns, signal transduction, and gene expression in the context of neurodegenerative diseases.

    Alzheimer’s disease-on-chips

    The application of microfluidic chips in Alzheimer’s disease research has provided valuable insights into distinct pathogenic features, including amyloid-beta and tau protein accumulation, mitochondrial dysfunction, and neuroinflammation.

    Several models of neurons-on-a-chip have been used to study tau propagation and amyloid-beta toxicity. By separating the soma and neurites, neurons-on-a-chip allow real-time visualization of proteinopathy.

    A gradient chip with interstitial flow has been used to study the effect of amyloid-beta oligomers on neurons. Inflammatory cytokine-mediated migration of microglia towards Alzheimer’s disease neurons and astrocytes has been observed using a 3D static neuroinflammation-on-a-chip model.

    Blood-brain barrier-on-a-chip has been developed to fully recapitulate amyloid plaque formation, neurofibrillary tangle formation, and increased permeability of the brain endothelial cells.

    Dynamic neurospheroid-on-a-chip has been developed by incorporating an osmotic pump that creates a flow of exogenous amyloid-beta to study axonal degeneration and cell death.

    Parkinson’s disease-on-chips

    Many studies have been conducted using Parkinson’s disease-on-a-chip to primarily recapitulate alpha-synuclein-related pathogenesis. The propagation of alpha-synuclein has been studied by co-culturing neuroglioma cells that express green fluorescent protein-tagged alpha-synuclein.

    A gradient chip has been developed to manipulate intracellular alpha-synuclein expression in singularly trapped yeasts in the system with a galactose gradient. Dopaminergic neurons-on-a-chip have been developed to recapitulate mitochondrial dysfunction and neural degeneration caused by Parkinson’s disease-related mutations.     

    Substantia nigra and vascular barrier chips have been developed by co-culturing human-induced pluripotent stem cell-derived midbrain dopaminergic neurons, primary glia cells, and brain microvascular endothelial cells in chambers separated by porous membrane. This model has been used to study blood-brain barrier-on-a-chip dysfunction, progressive neuronal loss, neuroinflammation, and astrogliosis.  

    Amyotrophic lateral sclerosis on-chips

    Application of chemotactic and volumetric gradients on amyotrophic lateral sclerosis-on-chips has caused the successful formation of interactions between FUS-mutated motor neurons and mesangioblast-derived myotubes through microchannels.

    Many pathologies of amyotrophic lateral sclerosis have been recapitulated by co-culturing TAR DNA-binding protein 43 (TDP-43)-mutated motor neuron spheroid and muscle fibers in a 3D condition between two separate chambers.  

    A three-chamber-chip has been developed to create metabolic interactions between superoxide dismutase-mutated astrocytes and cortical neurons through microchannels in a glutamate gradient condition. 

    Muscle denervation pathology of amyotrophic lateral sclerosis has been studied using an open compartmentalized neuromuscular junction device that co-cultures optogenetic motor neurons and superoxide dismutase-mutated astrocytes as a spheroid.

    Huntington’s disease on-chips

    Early pathologies of Parkinson’s disease have been studied by forming synaptic connections between cortical axons and striatal dendrites through microchannels of different lengths and a separate synaptic channel.

    Corticostriatal on-a-chip has been developed to study how mutant huntingtin protein reduces the cortical axonal transport of brain-derived neurotrophic factors to trigger striatal neuron degeneration.

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