Antecedent events underlying axon damage in an animal model of multiple sclerosis

Multiple sclerosis is a progressive autoimmune disease where myelin is gradually stripped from axons. Axon degeneration inevitably follows protracted myelin loss ultimately leading to irreversible neurological decline. To better understand the cellular mechanisms associated with the axon loss phase of the disease, spinal cord axons from the experimental autoimmune encephalomyelitis (EAE) animal model of multiple sclerosis were examined using correlated in vivo time-lapse microscopy and serial section transmission electron microscopic (ssTEM) reconstruction. A novel technique, termed near infrared burning (NIRB), was developed that took advantage of a femtosecond-pulsed mode locked laser’s ability to create photoconvertable fiducial markers for routine identification of previously imaged axons for ssTEM reconstruction. This combination of imaging techniques revealed the subcellular milieu that underlies axon degeneration at both the light and electron microscopic level. In particular, paranodal regions of axons in EAE animals contained a significantly higher population of mitochondria with large rounded, electron lucid, vesiculated mitochondria with unorganized cristae compared to controls. This effect was largely restricted to the paranodal region and was not always associated with direct immune cell interaction or myelin loss. Together, these results suggest a novel mechanism for axon degeneration that is not only focal in nature, but decoupled with myelin loss in the EAE animal model of multiple sclerosis.Thesis (M.S.)Department of Biolog

Irisin mRNA and circulating levels in relation to other myokines in healthy and morbidly obese humans

Objective: Skeletal muscle is considered to be an endocrine organ that secretes a number of myokines including follistatin (FST), myostatin (MSTN), activin A, and the newly identified irisin. Irisin's biology and function exhibit similarities with the functions of the FST-MSTN-activin A axis. It remains unknown whether there is any interplay among these molecules. The aim of this study is to examine potential associations of irisin with the FST, MSTN, and activin A axis. Methods: Two observational studies were performed to evaluate the associations of irisin with the other three peptides. Study A included 150 healthy males aged 18.48G0.16 years with BMI 23.18±3.75 kg/m2. Fasting serum samples were used to measure the levels of the molecules of interest. Study B included 14 morbidly obese individuals, candidates for bariatric surgery, aged 53.14±8.93 years with BMI 50.18±10.63 kg/m2. Blood samples were obtained after an overnight fast. Eight out of the 14 participants consented to an optional thigh biopsy during their bariatric surgery. Using the above blood and tissue samples, we measured circulating levels and muscle mRNA of irisin, FST, MSTN, and activin A. Results: We report that FNDC5 mRNA in muscle is positively correlated with FST mRNA expression in morbidly obese subjects (ρ=0.93, P<0.001). We also found that circulating irisin is positively correlated with FST circulating levels among lean subjects (ρ=0.17, P=0.05) while this association was suggestive among the obese (ρ=0.56, P=0.07). Conclusion: The newly identified myokine irisin may be positively associated with FST at both the mRNA and circulating protein level

Irisin mRNA and circulating levels in relation to other myokines in healthy and morbidly obese humans

Objective: Skeletal muscle is considered to be an endocrine organ that secretes a number of myokines including follistatin (FST), myostatin (MSTN), activin A, and the newly identified irisin. Irisin's biology and function exhibit similarities with the functions of the FST-MSTN-activin A axis. It remains unknown whether there is any interplay among these molecules. The aim of this study is to examine potential associations of irisin with the FST, MSTN, and activin A axis. Methods: Two observational studies were performed to evaluate the associations of irisin with the other three peptides. Study A included 150 healthy males aged 18.48G0.16 years with BMI 23.18±3.75 kg/m2. Fasting serum samples were used to measure the levels of the molecules of interest. Study B included 14 morbidly obese individuals, candidates for bariatric surgery, aged 53.14±8.93 years with BMI 50.18±10.63 kg/m2. Blood samples were obtained after an overnight fast. Eight out of the 14 participants consented to an optional thigh biopsy during their bariatric surgery. Using the above blood and tissue samples, we measured circulating levels and muscle mRNA of irisin, FST, MSTN, and activin A. Results: We report that FNDC5 mRNA in muscle is positively correlated with FST mRNA expression in morbidly obese subjects (ρ=0.93, P<0.001). We also found that circulating irisin is positively correlated with FST circulating levels among lean subjects (ρ=0.17, P=0.05) while this association was suggestive among the obese (ρ=0.56, P=0.07). Conclusion: The newly identified myokine irisin may be positively associated with FST at both the mRNA and circulating protein level