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Researchers at the National Institutes of Health (NIH) have identified a protein as a possible candidate mediating exercise intolerance associated with chronic fatigue syndrome.
On chronic fatigue syndrome
What is chronic fatigue syndrome? Chronic fatigue syndrome, also known as myalgic encephalomyelitis (ME), is a disorder that results in extreme tiredness, especially after physical or mental exertion. People with this condition are encumbered with overwhelming exhaustion to the point that they cannot perform or complete their usual daily physical activities. Other common symptoms of this disorder include headaches, dizziness, muscle aches, joint pain, and problems with memory and thinking. These symptoms last for six months or longer. In the United States, an estimated 2.5 million people are affected by this disorder.
The causes of chronic fatigue syndrome are poorly understood. Research investigations have suggested that the condition can be triggered by infections, stress, low blood pressure or changes in how the body utilizes energy. Currently, there are no known cures for this disorder. Individuals with chronic fatigue syndrome are typically dispensed with medications that treat their symptoms. For example, Advil is prescribed to treat pain. Counseling is provided to assist patients with managing their physical activities and sleep.
Identification of a potential cause of and molecular target for treating exercise intolerance linked to chronic fatigue syndrome
Evidence linking a protein to exercise intolerance in chronic fatigue syndrome came from the research conducted by Wang and colleagues at the NIH. They recruited a 38-year-old woman who had been diagnosed with cancer and chronic fatigue syndrome together with her 34-year-old male sibling who was free of cancer and chronic fatigue syndrome.
The researchers analyzed the ability of her skeletal muscle tissue to produce energy following aerobic exercise. Previous studies have implicated defects in energy generation and lowered oxygen consumption in muscle cells of chronic fatigue syndrome patients following aerobic exercise. Examination of the woman’s skeletal muscle tissue demonstrated a lowered oxygen consumption post-exercise compared to her brother’s skeletal muscle tissue. They also showed that the defect in energy generation lies within the cellular compartment or cellular “organ” known as mitochondria, which is the cell’s powerhouse and is responsible for producing energy for the cell’s needs. Further analysis led the researchers to determine that high levels of a protein, known as Wiskott-Aldrich Protein Family Member 3 (WASF3), inhibited respiration and oxygen consumption in the mitochondria.
The researchers at NIH also tested mice genetically engineered to produce high levels of WASF3 protein in their tissues. Compared to normal mice, the engineered mice exhibited reduced exercise capacity. This result suggests that the high levels of WASF3 protein had disrupted normal oxygen consumption and energy production in skeletal muscle tissues.
Further experiments showed that the WASF3 protein interfered with energy production by inhibiting the assembly of protein supercomplexes required for respiration and energy generation in the mitochondria. The scientists also confirmed the presence of high levels of the WASF3 protein in individuals with chronic fatigue syndrome when they studied the skeletal muscle tissues of these patients as compared to those of healthy individuals.
The WASF3 protein had been previously shown to be associated with a cellular response called the unfolded protein response. The unfolded protein response is activated in the cell in response to an accumulation of proteins that are wrongly or not folded. Exposing cells of the 38-year-old woman to inducers of the unfolded protein response resulted in an elevation of WASF3 protein levels. In contrast, treatment of the woman’s cells with suppressors of the unfolded response decreased the levels of the WASF3 protein. The scientists also detected an elevation in oxygen consumption rates, energy production, and in levels of respiratory protein supercomplexes in response to treatment with drugs that suppressed the unfolded protein response.
Given that no known treatments are available for chronic fatigue syndrome, these exciting findings may open up possible avenues for drug development targeting the WASF3 protein to treat patients with this condition.
References
https://www.mayoclinic.org/diseases-conditions/chronic-fatigue-syndrome/symptoms-causes/syc-20360490
Myhill S, Booth NE, McLaren-Howard J. Chronic fatigue syndrome and mitochondrial dysfunction. Int J Clin Exp Med. 2009;2(1):1-16. Epub 2009 Jan 15.
Vermeulen RC, Vermeulen van Eck IW. Decreased oxygen extraction during cardiopulmonary exercise test in patients with chronic fatigue syndrome. J Transl Med. 2014 Jan 23;12:20. doi: 10.1186/1479-5876-12-20.
Wang PY, Ma J, Kim YC, Son AY, Syed AM, Liu C, Mori MP, Huffstutler RD, Stolinski JL, Talagala SL, Kang JG, Walitt BT, Nath A, Hwang PM. WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome. Proc Natl Acad Sci U S A. 2023 Aug 22;120(34):e2302738120. doi: 10.1073/pnas.2302738120. Epub 2023 Aug 14. Assessed and Endorsed by the MedReport Medical Review Board