Can miRNA Measure Your Fitness?

 

By Maggie Kuo

We are constantly encouraged, or nagged, to exercise to promote good health.  But how much exercise is enough?  We finally might be able to precisely measure this threshold.

 

The research group lead by Thomas Thum at the Hannover Medical School in Hannover, Germany has been studying the use of microRNAs (miRs), noncoding RNAs that repress gene expression, to treat cardiovascular diseases.  As a side project, the group wondered if miRs could be used as an indicator of physical fitness.  The researchers found that a single session of endurance exercise increased the amount of miRs associated with the skeletal muscle.  Moreover, the amount of these miRs did correlate with fitness level.

 

Physical endurance is generally measured by maximum oxygen uptake (VO2max), the amount of oxygen used by the skeletal muscles during maximum effort exercise.  VO2max increases with fitness level.  How much an exercise regimen will raise VO2max depends greatly on the individual’s genes so the outcomes in one person cannot necessarily be applied to another person.  As a result, researchers in the exercise physiology field have been exploring the effects of exercise directly on gene expression.

 

miRs can be specific to the organ, like the heart, or to the biological process, like inflammation.  miRs are also stable outside of the cell and can therefore be detected in the blood plasma.  Several studies reported changes in plasma miR levels after exercise.  The miRs corresponded with skeletal and heart muscle adaptations and the levels were influenced by the intensity, type, and duration of the exercise protocol.

 

Thum and colleagues measured the amount of heart and skeletal muscle-associated miRs in blood samples from experienced marathon runners.  Blood was drawn two days before the race and immediately and 24 hours after the runner finished the course.  The researchers also recorded VO2max and anaerobic lactate threshold (VIAS), another physical fitness indicator, for each runner.  They found that the skeletal muscle miRs, miR-1, -133a, and -206, were higher shortly after the run and remained elevated 24 hours after the race.  The heart muscle miRs, miR-208b and -499, were also higher immediately after the run but returned to pre-race levels after 24 hours.   What intrigued the researchers the most was that the levels of all three skeletal muscle miRs trended with both VO2max and VIAS.  Runners with greater VO2max and VIAS, meaning they were more fit, tended to have higher amounts of skeletal muscle miRs in their blood plasma.  The researchers then compared the gene targets of the five miRs they measured against a list of 56 genes associated with physical endurance.  The heart miRs only modulated one gene on the list.  However, the skeletal muscle miR-1 regulated 8 genes and -206 regulated 10 genes, suggesting that enhanced fitness was due to increased regulation of physical endurance genes from the higher miR levels.  The researchers concluded that these skeletal muscle miRs could potentially be used as biomarkers of physical fitness.

 

More work needs to be done to confirm the accuracy of miRs as biomarkers, including measuring the amount of the miRs directly in the skeletal muscle, studying how the miR levels change with different exercise protocols, and determining if other miRs are influenced by endurance.  Nevertheless this study provides a potential new metric to evaluate physical fitness.  This metric could be used to establish more precise recommendations on exercise routines to promote better health.

Tumor-Suppressive microRNAs

 

By Thalyana Smith-Vikos

MicroRNAs (miRNAs) are short, noncoding RNAs that inhibit the expression of specific target genes. Certain classes of miRNAs have been identified as tumor suppressors, most notably miR-34. Studies have shown that miR-34 can be delivered as a tumor-static agent, including a 2012 report by Kasinski and Slack in Cancer Research. This report identifies miR-34 as a tumor suppressor in a Kras;p53 mouse model of lung cancer, the most potent cause of cancer deaths around the world. Tumors harvested from these mice had elevated levels of miR-34 targets, including Met and Bcl-2, indicating that miR-34 expression was inhibited. By adding exogenous miR-34, both tumor formation and progression of preformed tumors were prevented in the mice, and proliferation and invasion of lung tumor-derived epithelial cells were inhibited. This and other studies show promise for the use of miRNAs, especially miR-34, in clinical trials for cancer treatment and prevention.

Cancer Prevention: Affecting Epigenetic Changes with Diet

 

By Kelly Jamieson Thomas

Ending cancer needs to become a global health priority. Cancer, the leading cause of death worldwide, caused 8.2 million deaths in 2012. With 575,000 deaths attributable to cancer in 2010 in the United States, cancer-related deaths in the US are second only to those caused by heart disease, which caused 594,000. Bringing worldwide support behind ending cancer is one of the goals of World Cancer Day this February 4th. How can we end cancer? First and foremost, focus on prevention—the most viable option as a cure.

Historically, cancer has been perceived as a disease in which our genetic makeup dictates our likelihood of developing cancer. Presently, it has become broadly recognized that the initiation and progression of cancer is an intricate web of both genetic makeup and epigenetic events that alter our gene expression. Many studies have proven that epigenetic alterations are key components of the initiation and progression of cancer. These epigenetic processes—including DNA methylation, histone modification, and microRNA expression—are potentially reversible.

Global hypomethylation is a hallmark of almost all human cancers. CpG island hypermethylation and down-regulation is common for many genes involved in a broad range of functions that are deregulated in cancer. As a result, a breadth of research is now dedicated exclusively to understanding how epigenetic alterations are involved in the earliest stages of tumor progression in order to develop epigenetic-based cancer prevention strategies. NIH funding for epigenetic research has dramatically increased from approximately $500,000 to more than $13 million dollars. Support for pinpointing the relationship between diet, exercise, and cancer prevention is clearly on the rise.

Is it possible to affect epigenetic changes through our diet? Dietary compounds have been shown to elicit epigenetic changes in cancer cells. To fully understand how we can modulate cancer prevention through lifestyle, research must focus on how diet and bioactive food components specifically impact epigenetic processes. Antioxidants such as carotenoids and fiber found in many vegetables and fruit offer a variety of anti-cancer benefits. Increased dietary folate, a soluble form of B6 vitamin, consumption has been linked to a decrease in colorectal cancer through its affect on DNA methylation. Dietary phytochemicals, that act as anti-cancer agents (including polyphenols, genistein, sulforaphane, resveratrol, and curcumin) have been shown to act through epigenetic mechanisms.

Population studies are also instrumental in linking diet and cancer prevention. Through the American Cancer Society’s Cancer Prevention Study-3, more than 300,000 men and women ranging from 30-65 years old with no personal history of cancer are participating in an epidemiological cohort study to examine the interplay between genetics, lifestyle, behavior, environment, blood factors, and waist circumference in relation to cancer risk. Large epidemiological studies in combination with rigorous scientific studies help unravel the mechanisms of cancer initiation and progression.

Cancer prevention is the best way to ultimately cure the disease. To work towards cancer prevention, we must further explore how dietary modifications may achieve epigenetic reprogramming, resulting in the maintenance of normal gene expression and reversal of tumor progression.

 

Leafing Through The Literature

Thalyana Smith-Vikos

Highlighting recently published articles in molecular biology, genetics, and other hot topics

 

Aging is inherited maternally

 

Credit: Bob AuBuchon (Flickr)
Credit: Bob AuBuchon (Flickr)

Ross and colleagues investigated how mitochondrial DNA (mtDNA) mutations, which are exclusively maternally inherited, can contribute to aging. The researchers found that these mutations result in mild aging in otherwise wild-type mice, while decreasing fertility and accelerating premature aging in respectively heterozygous and homozygous PolgA mutants with increased mtDNA mutations. Additionally, maternal and somatic mtDNA mutations also resulted in brain developmental disorders. The authors posit that aging tissues may arise from the rapid expansion of mutated respiratory chain factors as mutated mtDNA replicates.

 

MicroRNAs regulate micro food portions

Vora et al. have identified a conserved microRNA (miRNA), miR-80, which regulates dietary restriction in C. elegans. Similar to dietary restriction-mediated effects, these mir-80 mutant worms are long-lived and maintain a healthy state for a prolonged period, regardless of the presence of food. Transcription factors DAF-16 and HSF-1 and transcription co-factor CBP-1 are required for these mir-80 mutant phenotypes. Expression of this miRNA is decreased when worms are subjected to a restricted diet, resulting in increased levels of CBP-1.

 

A fatty reward

Credit: Quinn Dombrowski (Flickr)
Credit: Quinn Dombrowski (Flickr)

Researchers have proposed that lowered dopaminergic function from a high-fat diet leads to obesity by promoting excessive food intake to restore this food-reward relationship. Tellez et al. further investigated how a high-fat diet can affect dopamine levels. The authors identified an intestinal lipid messenger, oleoylethanolamine, which is normally suppressed under a high-fat diet but can restore dopamine release upon administration. Additionally, administration of oleoylethanolamine increased consumption of low-fat foods, indicating that this signaling molecule may be responsible for promoting reward of low-fat foods.

 

Pathogen-host relationship therapy

C. albicans can exist as part of the non-pathogenic gastrointestinal microbiota or can be pathogenic to mammals. Pande and colleagues report that, while this pathogenic switch is due to the host’s suppressed immune system, a microbial genetic program is also at play. The researchers found that passage of C. albicans through the gut results in a switch to commensalism, driven by the transcription factor Wor1. These C. albicans cells that have transitioned into a commensal state are phenotypically different and express a unique transcriptome. The findings suggest that disrupting this genetic program results in reversion to a pathogenic state.

 

Breakthrough in wheat stem rust resistance

A highly resistant race of wheat stem rust, Ug99, has been plaguing wheat production areas all over the world for a number of years. Saintenac et al. report that the Sr35 gene cloned from T. monococcum provides near resistance to Ug99 and similar races, and the gene can be successfully transferred to polyploidy wheat. Periyannan et al. similarly identified a resistance gene, Sr33, which was cloned from another wild relative, A. tauschii. Both Sr33 and Sr35 encode coiled-coil, nucleotide-binding, leucine-rich repeat proteins that resemble other pathogen resistance proteins.

 

Transcribing autism genes

King and colleagues have provided a link to a recent correlation between mutated topoisomerases in individuals with autism and other autism spectrum disorders (ASDs). The researchers showed that a topoisomerase inhibitor, topotecan, reduces the expression of ASD-associated genes in a dose-dependent manner. Intriguingly, these ASD candidate genes are substantially longer than other genes on average. Topectan specifically prevents transcriptional elongation of extremely long genes (>200 kb), which was also achieved by knocking down topoisomerase 1 or 2b in neurons.

Leafing Through The Literature

Thalyana Smith-Vikos

Highlighting recently published articles in molecular biology, genetics, and other hot topics

Battle of the Small RNAs

Sarkies et al. have analyzed gene expression in the nematode C. elegans upon infection with the positive-strand RNA virus Orsay. As RNAi is required for the immune response, the Argonaute protein RDE-1exhibits less repression of its endogenous small RNA targets to focus on its exogenous target. The authors also showed that a wild C. elegans isolate exhibits a reduction in miRNA expression and a consequent increase in miRNA target levels upon viral infection.

Continue reading “Leafing Through The Literature”

Leafing through the Literature

Thalyana Smith-Vikos

Highlighting recently published articles in molecular biology, genetics, and other hot topics

Small Molecules Achieve Pluripotency

Hou et al. have reached uncharted territory in stem cell research: rather than achieving pluripotency using the well-established transcription factor cocktail or recent advances in somatic cell nuclear transfer, mouse somatic cells were reprogrammed to generate pluripotent stem cells with a frequency of 0.2% using a cocktail of seven small molecules. These reprogrammed cells, termed chemically induced pluripotent stem cells (CiPSCs), were shown to resemble embryonic stem cells (ESCs) based on gene expression and epigenetic profiling, which is not case for other types of iPSCs.

Tissue and Organ Generation from Pluripotency

Takebe et al. report the first case of successful generation of a three-dimensional vascularized organ  Continue reading “Leafing through the Literature”