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Exercise fatigue in mice - the mechanism behind it and how virus could be involved

Discussion in 'Other Health News and Research' started by natasa778, Apr 30, 2010.

  1. natasa778

    natasa778 Senior Member

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    London UK
    advance warning: these ones are quite geeky - hoping that Gerwyn or someone could explain in plain English (I can't sorry)

    Remodeling of ryanodine receptor complex causes “leaky” channels: A molecular mechanism for decreased exercise capacity http://www.pnas.org/content/105/6/2198.long


    retrovirus-induced dysfuntion of ryanodine receptor complex:

    HIV-1 Tat Activates Neuronal Ryanodine Receptors with Rapid Induction of the Unfolded Protein Response and Mitochondrial Hyperpolarization
    http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19009018
    Neurologic disease caused by human immunodeficiency virus type 1 (HIV-1) is ultimately refractory to highly active antiretroviral therapy (HAART) because of failure of complete virus eradication in the central nervous system (CNS), and disruption of normal neural signaling events by virally induced chronic neuroinflammation. We have previously reported that HIV-1 Tat can induce mitochondrial hyperpolarization in cortical neurons, thus compromising the ability of the neuron to buffer calcium and sustain energy production for normal synaptic communication. In this report, we demonstrate that Tat induces rapid loss of ER calcium mediated by the ryanodine receptor (RyR), followed by the unfolded protein response (UPR) and pathologic dilatation of the ER in cortical neurons in vitro. RyR antagonism attenuated both Tat-mediated mitochondrial hyperpolarization and UPR induction. Delivery of Tat to murine CNS in vivo also leads to long-lasting pathologic ER dilatation and mitochondrial morphologic abnormalities. Finally, we performed ultrastructural studies that demonstrated mitochondria with abnormal morphology and dilated endoplasmic reticulum (ER) in brain tissue of patients with HIV-1 inflammation and neurodegeneration. Collectively, these data suggest that abnormal RyR signaling mediates the neuronal UPR with failure of mitochondrial energy metabolism, and is a critical locus for the neuropathogenesis of HIV-1 in the CNS. PMID: 19009018
     

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