Abstract
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that involves the autoreactive T-cell attack on axonal myelin sheath. Lesions or plaques formed as a result of repeated damage and repair mechanisms lead to impaired relay of electrical impulses along the nerve, manifesting as clinical symptoms of MS. Evidence from studies in experimental autoimmune encephalomyelitis (EAE) models of MS strongly suggests that mitochondrial dysfunction presents at the onset of disease and throughout the disease course. The aim of this study was to determine if mitochondrial dysfunction occurs before clinical symptoms arise, and whether this is confined to the CNS. EAE was induced in C57B/L6 mice, and citrate synthase and mitochondrial respiratory chain (MRC) complex I–IV activities were assayed at presymptomatic (3 or 10 days post first immunisation (3 or 10 DPI)) and asymptomatic (17 days post first immunisation (17 DPI) time-points in central nervous system (CNS; spinal cord) and peripheral (liver and jaw muscle) tissues. Samples from animals immunised with myelin oligodendrocyte glycoprotein (MOG) as EAE models were compared with control animals immunised with adjuvant (ADJ) only. Significant changes in MOG compared to control ADJ animals in MRC complex I activity occurred only at presymptomatic stages, with an increase in the spinal cord at 10 DPI (87.9%), an increase at 3 DPI (25.6%) and decrease at 10 DPI (22.3%) in the jaw muscle, and an increase in the liver at 10 DPI (71.5%). MRC complex II/III activity changes occurred at presymptomatic and the asymptomatic stages of the disease, with a decrease occurring in the spinal cord at 3 DPI (87.6%) and an increase at 17 DPI (36.7%), increase in the jaw muscle at 10 DPI (25.4%), and an increase at 3 DPI (75.2%) and decrease at 17 DPI (95.7%) in the liver. Citrate synthase activity was also significantly decreased at 10 DPI (27.3%) in the liver. No significant changes were observed in complex IV across all three tissues assayed. Our findings reveal evidence that mitochondrial dysfunction is present at the asymptomatic stages in the EAE model of MS, and that the changes in MRC enzyme activities are tissue-specific and are not confined to the CNS.
Highlights
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) which has a heterogeneous clinical presentation with symptoms including impaired vision, spasms, fatigue and muscle weakness [1]
We investigated whether evidence of mitochondrial respiratory chain (MRC) dysfunction may be present in peripheral tissues in addition to that of the CNS
A possible reason to account for the apparent preservation of MRC complex IV activity may reflect the time course of the present study with the final tissue samples being taken 17 days DPI; this may have been an insufficient period of time to detect any evidence of an impairment in enzyme activity and future studies may be required to elucidate this possibility
Summary
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) which has a heterogeneous clinical presentation with symptoms including impaired vision, spasms, fatigue and muscle weakness [1]. Clinically defined as the autoreactive T-cell attack on axonal myelin sheath, the pathophysiological mechanisms resulting in fatigue and weakness have yet to be fully elucidated [5]. In view of the central role that mitochondria play in cellular energy production, there has been speculation that an impairment in the function of this organelle may contribute to the fatigue and muscle weakness presented in MS, since fatigue and weakness are hallmarks of mitochondrial dysfunction [6,7]. Structural and functional abnormalities in cortico-subcortical circuits have been suggested as contributory factors to fatigue in MS [9], the exact cause of fatigue and weakness in MS still remains to be fully elucidated
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