Research Research Digest Research Digest 10/09/21 Welcome to the 76th Emerge Australia Research Digest, where you will find summaries of some of the latest research and information about ME/CFS, with links to the complete articles. You can also join our community and choose to have the Digest delivered straight to your inbox every fortnight on a Friday afternoon by signing up to our mailing list here. We appreciate the support of everyone who reads the Digest – we encourage regular subscribers to support us with a monthly suggested donation of $2. You can sign up for monthly giving here. _______________________________________________________________________________________________________ Potential Therapeutic Benefit of Low Dose Naltrexone in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Role of Transient Receptor Potential Melastatin 3 Ion Channels in Pathophysiology and Treatment Authors: Cabanas H, Muraki K, Eaton-Fitch N, Staines DR, Marshall-Gradisnik S (Griffith University, Australia) Publication: Frontiers in Immunology Link: https://www.frontiersin.org/articles/10.3389/fimmu.2021.687806/full Although the pathomechanism of ME/CFS remains poorly understood, consistent immune dysfunction and abnormalities have been seen in Natural Killer (NK) cell function. These authors have also previously identified impairment in the Transient Receptor Potential Melastatin 3 (TRPM3) calcium (Ca2+) ion channel. Previous research has shown that activation of opioid receptors can inhibit the TRPM3 channel, and that opioids are immunosuppressant, presenting implications for calcium-dependent NK cell immune function. Naltrexone hydrochloride acts as an antagonist to the mu (μ)-opioid receptor, negating the inhibitory function of these opioid receptors on TRPM3 functioning. At low doses (3.0-5.0mg/day) it has been used as a treatment for ME/CFS. This study aimed to investigate the potential therapeutic effect of low-dose naltrexone (LDN) in restoring TRPM3 functioning in ME/CFS patients. Nine ME/CFS patients (Canadian Consensus Criteria) and nine age and sex matched healthy controls were included in the study. All ME/CFS patients had been taking LDN (3-5mg/day) for at least four weeks. All participants provided a blood sample and completed demographic and symptom questionnaires. NK cells were isolated, and TRPM3 ion channel activity measured using whole-cell patch-clamp technique. TRPM3 ion channel activity analysis found that ME/CFS patients taking LDN had similar TRPM3 channel activity to healthy controls. The authors conclude that the restoration of channel function and reported symptom improvement from LDN suggest that this may be the mechanism of therapeutic action of LDN in ME/CFS patients, and that LDN is of potential therapeutic benefit for ME/CFS patients. _______________________________________________________________________________________________________ Central Autonomic Network Disturbance in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Pilot Study Authors: Zinn MA, Zinn ML, Jason LA, (DePaul University, Center for Community Research, USA)Publication: NeuroRegulation Link: https://www.neuroregulation.org/article/view/21387 ME/CFS is known to have both central nervous system and autonomic nervous system involvement. The central autonomic network (CAN) includes several regions of the brain, including the cortex that controls peripheral autonomic nervous system functioning. This study aimed to quantify the effect of physical exertion on CAN function in ME/CFS using exact low-resolution electromagnetic tomography (eLORETA). eLORETA utilises scalp EEG signals to estimate cortical current density. The study included seven participants with ME/CFS (meeting both Fukuda criteria and Canadian Consensus Criteria) and six healthy controls (HC). Participants completed the DePaul Symptom Questionnaire (DSQ) and the Short Form Medical Outcomes Survey (SF-36) before undertaking a 3-minute repetitive submaximal handgrip protocol. EEG recordings were made for five minutes prior to handgrip, immediately following handgrip, and 24 hours post handgrip. Significant differences were found between the ME/CFS and HC groups for cortical current density post handgrip, which were even more pronounced 24 hours post handgrip. Cortical current density changes were particularly noticeable in the low alpha and low beta frequency subbands. The authors suggested that low alpha subbands influence processing of fatigue during physical activity, while low beta is linked to cognitive processing of attention. As this was a pilot study with a small sample size, the authors highlight that the results should be interpreted with caution. However, this study showed that eLORETA could be used to examine CAN structures involved in PEM, and has provided early evidence of CAN involvement in PEM in ME/CFS. The authors conclude that, if confirmed in further studies, this approach could be used to aid diagnosis and measure treatment efficacy. _______________________________________________________________________________________________________ Insights from myalgic encephalomyelitis/chronic fatigue syndrome may help unravel the pathogenesis of postacute COVID-19 syndrome Authors: Komaroff AL, Lipkin WI (Columbia University, USA) Publication: Trends in Molecular Medicine Link: https://www.sciencedirect.com/science/article/pii/S1471491421001349Some individuals experience lingering illness with fatigue and cognitive alterations following acute infection with the SARS CoV-2 virus. This is known as post-acute sequelae of SARS-CoV 2 infection (PASC), colloquially long-COVID, and shares features with ME/CFS which also commonly develops following acute infectious disease. This article summarised what is currently known about the pathogenesis of ME/CFS and of ‘acute’ COVID-19 and proposes a potential pathogenesis for PASC. ME/CFS has been described in medical literature for over 200 years, with reports of precipitating acute infection from a wide variety of infectious agents, suggesting that an abnormal response to infection may be present in affected individuals. Previous research has also identified a potential relationship between the microbiome, gut inflammation and ME/CFS symptoms, although it is not yet known if this is a cause or consequence of the condition. A range of immunologic, metabolic, and nervous system abnormalities have also been observed. COVID-19 has been seen to cause multi-organ pathology during acute illness. Many COVID-19 patients have reported persistent symptoms 6 months post-infection, including persistent respiratory, cardiovascular, nervous system, metabolic, and gastrointestinal system disorders significantly more often than the control subjects. Pathogenesis of PASC is currently being investigated, with some evidence that, like ME/CFS, autoantibodies or autonomic dysfunction may be contributing to symptoms. Finally, the authors propose a research agenda for ME/CFS and PASC, which includes further defining individual components of pathogenesis of ME/CFS and the interaction of these components, and whether the pathophysiology found in post-COVID-19 syndrome is similar to that of ME/CFS. _______________________________________________________________________________________________________ Research Interview: Professor Ken Walder Authors: Murphy J Publication: Emerge Australia Link: https://www.emerge.org.au/blog/professor-ken-walder In 2020 Australia’s National Health and Medical Research Committee allocated $3.3million in funding for ME/CFS research. One of the three funding recipients was Professor Ken Walder. Currently the Chair of Metabolic Diseases at Deakin University, and with experience as an inventor on 40 patents and author on over 150 academic papers, Walder is bringing the extensive experience from his long career to ME/CFS. With a particular interest in mitochondria, Walder hypothesises that the fatigue and some other symptoms associated with ME/CFS may be the result of a systematic problem with the ability of mitochondria to produce the energy required by the body. The title of Walder’s grant submission was “Using ‘omics to unravel the pathophysiology and repurpose drugs to treat ME/CFS.” His project will start by identifying what is wrong with ME/CFS cells, and then test drugs to see which are most able to reverse the problems identified in the cells. Walder intends to apply stress to the most energy-hungry cells (skeletal muscle and brain cells via use of stem cells), an area previously overlooked by most research. After learning how to stress and dysregulate ME/CFS cells, Walder will seek to trial 1300 well-known, off-patent drugs to identify which can best restore ME/CFS cells to the appearance of healthy control cells. If successful, it is possible that patients could be taking part in the trial of experimental drugs by the end of the decade.