Author Interviews, Exercise - Fitness, Karolinski Institute, PLoS / 26.09.2016
Is Muscle Memory a Myth?
MedicalResearch.com Interview with:
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Dr. Maléne Lindholm[/caption]
Maléne Lindholm, PhD
Karolinska Institutet
Dept. of Physiology & Pharmacology
Stockholm Sweden
MedicalResearch.com: What is the background for this study?
Response: It is well known that exercise training provides marked health benefits and can prevent and treat a broad set of diseases. Therefore, a deeper understanding and characterization of the molecular processes behind training adaptation is essential for human health.
This study aimed at exploring the effects of endurance training on the human skeletal muscle transcriptome (activity of all genes) and investigate the possible presence of a muscle memory of training. To do this, the healthy volunteers in this study first trained only one leg, 4 times per week for 3 months. After 9 months of detraining, the subjects then came back and trained both legs in the same way as during the first training period, thus one leg was then previously well-trained and one previously untrained. This meant that each individual was their own control, as both legs have the same genome, experience the same stress, diet etc. Only the training status differed.
Dr. Maléne Lindholm[/caption]
Maléne Lindholm, PhD
Karolinska Institutet
Dept. of Physiology & Pharmacology
Stockholm Sweden
MedicalResearch.com: What is the background for this study?
Response: It is well known that exercise training provides marked health benefits and can prevent and treat a broad set of diseases. Therefore, a deeper understanding and characterization of the molecular processes behind training adaptation is essential for human health.
This study aimed at exploring the effects of endurance training on the human skeletal muscle transcriptome (activity of all genes) and investigate the possible presence of a muscle memory of training. To do this, the healthy volunteers in this study first trained only one leg, 4 times per week for 3 months. After 9 months of detraining, the subjects then came back and trained both legs in the same way as during the first training period, thus one leg was then previously well-trained and one previously untrained. This meant that each individual was their own control, as both legs have the same genome, experience the same stress, diet etc. Only the training status differed.
Ambika Satija[/caption]
Ambika Satija
Departments of Nutrition & Epidemiology
Harvard T. H. Chan School of Public Health
Boston, MA
MedicalResearch.com: What is the background for this study?
Response: In this study, we followed more than 200,000 male and female health professionals across the U.S. for more than 20 years who had regularly filled out questionnaires on their diet, lifestyle, medical history, and new disease diagnoses as part of three large long-term studies.
Amanda Sierra, PhD
Research Professor and Group Leader
Ramón y Cajal Fellow
Achucarro Basque Center for Neuroscience
Laida Bidea
Bizkaia Science and Technology Park
Zamudio, Bizkaia, Spain
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Sierra: Microglia phagocytosis of apoptotic cells is at the core of the brain regenerative response to recover the homeostasis of the brain parenchyma after damage because it prevents the spillover of toxic intracellular contents and is actively anti-inflammatory. However, while neuronal death is widespread in neurodegenerative diseases (Alzheimer´s, Parkinson´s, multiple sclerosis) and well as in ischemic and traumatic brain injuries, we have a complete lack of knowledge of the efficiency of microglial phagocytosis in the diseased brain.
In this paper we have discovered that microglia have a generalized response to apoptotic challenges: when confronted to a rise in the number of newborn cells, microglia display a combination of different strategies to boost their phagocytic output: increase the phagocytic capacity of each cell, recruit more cells to become phagocytic, or increase the total number of microglia (Abiega et al., PLoS Biol 2015). Thus, microglia have a very large potential for phagocytosis that could be summoned when needed.
To our surprise, however, in pathological conditions such as epilepsy (mouse and human), microglial phagocytosis was blocked. We have made use of the adult neurogenic cascade, where newborn cells undergo apoptosis naturally and are engulfed by “unchallenged microglia” (Sierra et al. Cell Stem Cell 2010), to establish the baseline of microglial phagocytosis efficiency. Whereas in physiological conditions microglia phagocytose over 90% of the apoptotic cells and remove them in under 1.5h, soon after the seizures it only engulfed 10% of the apoptotic cells and took up to 6h to digest them. This is the first quantification of microglial phagocytosis efficiency in the diseased mouse and human brain..
The block in phagocytosis was a rather complex phenomenon related to an impaired recognition (reduction of phagocytosis receptors) as well as impaired motility and targeting (reduced basal motility). We have also shown that the impairment is mediated at least partially by altered ATP microgradients: ATP is not only a neuro- and gliotransmitter widely released during seizures but is also a well-known “find-me” signal released by apoptotic cells. Thus, during seizures microglia became “blinded” by the neuronal hyperactivity and could not find the apoptotic cells.
In addition, we have shown that impairing phagocytosis releases the break on the inflammatory response. In fact, the impaired microglia were in a pro-inflammatory state and produced more cytokines such as tumor necrosis factor alfa (TNFa) or interleukin-1beta (IL-1b), which are well known neurotoxic and epileptogenic factors.
Mallory Kidwell[/caption]
Mallory Kidwell, B.A.
Project Coordinator at the 
Dr. Katarina Truvé[/caption]
Katarina Truvé PhD
Swedish University of Agricultural Sciences and
Kerstin Lindblad-Toh
Uppsala University
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Truvé: Gliomas are malignant brain tumors that are rarely curable. These tumors occur with similar frequencies in both dogs and humans. Gliomas in dogs are strikingly similar at the biological and imaging level to human tumor counterparts. Some dog breeds such as Boxer and Bulldog are at considerably higher risk of developing glioma. Since these breeds at high risk are recently related, they are most likely carrying shared genetic risk factors. Our goal was therefore to use the dog genome to locate genes that may be involved in the development of glioma in both dogs and humans. We found a strongly associated locus and identified three candidate genes, DENR, P2RX7 and CAMKK2 in the genomic region. We have shown that CAMKK2 is lower expressed in glioma tumors than normal tissue in both dogs and human, and it has been reported that the associated canine mutation in P2RX7 results in a decrease in receptor function.
Dr. Alexander Turchin[/caption]
Alexander Turchin, MD, MS
Associate Physician, Brigham and Women's Hospital
Associate Professor of Medicine, Harvard Medical School
Brigham and Women's Hospital
Department of Medicine
Endocrinology
Boston, MA 02115
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Turchin: It is known that fewer women than men at high risk for cardiovascular disease are treated with statins.
However, the reasons for this sex disparity are not fully understood.
Our study identified 4 factors that accounted for over 90% of the difference in statin therapy between women and men with coronary artery disease:
Dr. Charu Kaushic[/caption]
Charu Kaushic. PhD.
Professor
OHTN Applied HIV Research Chair
Department of Pathology and Mol. Medicine
McMaster Immunology Research Center,
McMaster University
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Kaushic: Female sex hormones, estradiol and progesterone have been shown to regulate immune responses in many experimental and clinical studies. We and others have shown previously that these hormones also regulate susceptibility to and outcome of sexually transmitted infections (STIs), including Chlamydia, HSV-2, SIV and HIV-1. Most studies show that progesterone generally increases susceptibility while estradiol generally confers protection against STIs. This has recently gained much more widespread attention because of the controversy surrounding use of injectable hormonal contraceptives in geographical areas where there is high prevalence of HIV-1. The most frequently used injectable contraceptive uses a progestin-based formulation which has been correlated with 2-fold increase in HIV acquisition and transmission in epidemiological studies. Oral contraceptives that contain a combination of estradiol and progesterone do not show similar correlation with increased infection. This is currently a very important women’s health issue, which is being carefully monitored by many public health agencies, including WHO. Many researchers are focusing efforts in understanding how sex hormones can increase or decrease susceptibility of women to STIs.
We have published in this area for more than a decade, including a series of papers showing that in a mouse model, the outcome of genital herpes (HSV-2) infection can depend on which hormone we treat the mice with. A few years ago, we showed for the first time that mice that received an HSV-2 vaccine under the influence of estradiol were much better protected and showed less disease pathology (Bhavanam et al, Vaccine 2008). These results were reproduced a year later by another group, using an actual HSV-2 vaccine formulation. Since then, we have been working to understand at a cellular level, the underlying mechanism of estradiol-mediated enhanced protection. In this PLOS Pathogens paper, we report for the first time a cellular mechanism by which estradiol was seen to enhance immune protection against HSV-2 infection in mice.
The main findings are that estradiol primes dendritic cells in the vaginal tract to induce enhanced anti-viral T cell responses. Dendritic cells are key immune cells that decide what type of immune responses will be mounted against an infection. Under the influence of estradiol, the dendritic cells in the vaginal tract of mice induced Th17 cells which in turn helped enhance anti-viral T cell responses (Th1), resulting in better protection against genital HSV-2. This regulation of anti-viral immunity was seen only in the reproductive tract.
Dr. Haidong Zhu[/caption]
Haidong Zhu, MD, PhD
Associate Professor of Pediatrics
Georgia Prevention Institute
Medical College of Georgia
Augusta University
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Zhu: Vitamin D plays an important role in a wide range of body functions beyond bone health. Vitamin D deficiency is associated with increased risk of cancer and cardiovascular disease. Vitamin D deficiency is common among darker skin individuals, particularly African-Americans, which could contribute to health disparity. We want to understand underlying molecular mechanism (i.e. global DNA methylation) for how vitamin D deficiency causes cancer, cardiovascular disease and impaired immune function. DNA methylation, a chemical modification to our genome, is one of the ways that our body adapts to the environment. Low rate of global DNA methylation is a common event in cancer, which may lead to disturbances in the genome, make the genome more vulnerable to environmental damage and increase disease risk.
Our study shows that majority of black teens are vitamin D deficient and have a lower rate of global DNA methylation than white teens. We further demonstrate that vitamin D3 supplementation for 16 weeks increases global DNA methylation in black teens and young adults. Our study provides an important piece of evidence that vitamin D plays a role in epigenetic regulation in humans, which could be an underlying mechanism for vitamin D-deficiency related disease risk and health disparity.
