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  • Quantitative sensory testing QST is a

    2018-11-14

    Quantitative sensory testing (QST) is a standardized technique to assess human somatosensory function and document altered nociceptive signal processing (Backonja et al., 2013). By determining pain and detection threshold to external mechanical and thermal stimuli, sensory profiles are generated that can potentially trace underlying pathophysiological mechanisms. QST profiles have been made of patients with muscle-related disorders such as fibromyalgia, chronic back pain and myogenic temporomandibular disease revealing similarities as well as differences that may mirror distinct neurobiological mechanisms (Blumenstiel et al., 2011; Pfau et al., 2009). We used a comprehensive QST assessment to characterize the sensory phenotype of our cohort, a pre-requisite for identifying molecular signatures of muscle pain. Our analysis of the clinical and molecular profile of muscle pain in DM2 has enabled us to identify molecular signals in the affected muscle that segregate with muscle pain.
    Methods
    Results
    Discussion We provide compelling evidence that myalgia in DM2 patients could be initiated and maintained by molecular changes within the muscle. This interpretation is supported by our discovery that distinct transcriptome profiles segregate myalgic from non-myalgic patients. In principle miss-splicing of CNBP targets in the annexin v or other tissues could contribute to myalgia. However, if central nervous system mechanisms were primary a molecular signature for the presence of pain would not be expected in the muscle. Decreased pressure pain thresholds (PPT) in myalgic DM2 patients indicate that the myalgia could be initiated by peripheral mechanisms within the muscle (Graven-Nielsen and Arendt-Nielsen, 2010). Our data is supported by an earlier study that found lowered PPT in DM2 patients distinct from pain associated with other muscle disease (George et al., 2004). Peripheral sensitization mechanisms are prominent in muscle and are known to be a trigger for central sensitization (Graven-Nielsen and Mense, 2001; Lewin et al., 2014; Mense, 2003). Central sensitization was likely present in myalgic DM2 patients as evidenced by a slightly elevated wind-up compared to non-myalgic DM2 patients but not in healthy subjects. We further observed that sensation to non-painful stimuli in DM2 patients was suppressed, independent of the presence of muscle pain. There are various conditions associated with chronic muscle pain, fibromyalgia, low back and neck pain, and these disease entities show different sensory profiles as measured with psychometric methods. However, presentation of myalgia in DM2 patients may be easily misdiagnosed as fibromyalgia (Auvinen et al., 2008). In fibromyalgia there is a generalized mechanical and thermal hypersensitivity and touch modalities are usually unaffected (Blumenstiel et al., 2011). Wind-up ratio elevation has been observed in fibromyalgia syndrome (Staud et al., 2001). Thus there are differences but also similarities between the sensory profiles of myalgia due to DM2 disease and fibromyalgia. In contrast, QST profiles in chronic low back pain patients reveal localized alterations such as lowered PPT (Blumenstiel et al., 2011; Gerhardt et al., 2015). We noted however that few patients with DM2 with myalgia have generalized lowered mechanical and thermal (cold and heat) thresholds. Whether such spatial and modality spread in sensory profiles represents a separate pain processing mechanisms or related to disease progression remains to be clarified. The DM2 patients studied here showed no differences in age, current medication or histopathology of muscle tissue depending on whether they were myalgic or non-myalgic. Thus we have no evidence that the differences observed in the transcriptome of myalgic and non-myalgic DM2 muscle was based on anything else besides the presence of pain. It is known that certain types of ion channels are miss-spliced in myotonic dystrophies (Charlet-B et al., 2002; Tang et al., 2012). Abnormal splicing and downregulation of ubiquitin ligase, NEDD4, in DM2 patients prescribed HMG Co-A reductase inhibitors (statins) has been associated with adverse reactions (Screen et al., 2014). Also, hyperlipidemia and insulin resistance are common in DM2 patients, suggesting that elevated endogenous lipid levels could conceivably contribute to muscle pain in DM2 (Piomelli and Sasso, 2014; Heatwole et al., 2011).