Rehabilitation Improves Mitochondrial Energetics in Progressive Multiple Sclerosis: The Significant Role of Robot-Assisted Gait Training and of the Personalized Intensity.

Fabio Manfredini,Sofia Straudi,Veronica Tisato,Giovanna Marchetti,Nino Basaglia,Nicola Lamberti,Paolo Pinton,Nicole Ziliotto,Paola Secchiero,Simone Patergnani,Francesco Bernardi,Massimo Bonora

doi:10.3390/diagnostics10100834

Fabio Manfredini, Sofia Straudi + Show 10 more

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https://doi.org/10.3390/diagnostics10100834

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Journal: Diagnostics	Publication Date: Oct 17, 2020
Citations: 15	License type: CC BY 4.0

Affiliation: University of Ferrara, University of Milano-Bicocca

Abstract

Abnormal levels of pyruvate and lactate were reported in multiple sclerosis (MS). We studied the response of markers of mitochondrial function to rehabilitation in relation to type, intensity and endurance performance in severely disabled MS patients. Forty-six progressive MS patients were randomized to receive 12 walking sessions of robot-assisted gait training (RAGT, n = 23) or conventional overground therapy (CT, n = 23). Ten healthy subjects were also studied. Blood samples were collected to determine lactate, pyruvate, and glutathione levels and lactate/pyruvate ratio pre–post rehabilitation. In vivo muscle metabolism and endurance walking capacity were assessed by resting muscle oxygen consumption (rmVO2) using near-infrared spectroscopy and by six-minute walking distance (6MWD), respectively. The levels of mitochondrial biomarkers and rmVO2, altered at baseline with respect to healthy subjects, improved after rehabilitation in the whole population. In the two groups, an enhanced response was observed after RAGT compared to CT for lactate (p = 0.012), glutathione (<0.001), lactate/pyruvate ratio (p = 0.08) and rmVO2 (p = 0.07). Metabolic biomarkers and 6MWD improvements were exclusively correlated with a training speed markedly below individual gait speed. In severely disabled MS patients, rehabilitation rebalanced altered serum metabolic and muscle parameters, with RAGT being more effective than CT. A determinable slow training speed was associated with better metabolic and functional recovery. Trial Registration: ClinicalTrials.gov NCT02421731.

Highlights

Altered metabolic dynamics have frequently been observed in pathologic conditions and in several neurodegenerative disorders [1,2]
The patients included in this study were a subsample (n = 46) of those participating in the RAGTIME trial, a randomized controlled study that compared two different walking rehabilitation protocols in progressive multiple sclerosis (MS) patients with severe disability (NCT02421731) [32]
Of the 72 patients enrolled in the RAGTIME trial [32], 46 were considered in this secondary analysis

Summary

Introduction

Altered metabolic dynamics have frequently been observed in pathologic conditions and in several neurodegenerative disorders [1,2]. Several studies have associated biochemical changes (ATP production, oxygen levels and glucose availability) with multiple sclerosis (MS), a chronic inflammatory disease affecting the central nervous system [3,4]. Glucose catabolism through glycolysis produces pyruvate, which, under aerobic conditions, is oxidized in the mitochondria to produce 36 ATPs through the tricarboxylic acid cycle and oxidative phosphorylation [7]. Pyruvate is reduced to lactate in the cytoplasm and secreted into the extracellular space [7] in the presence of low oxygen availability or, in general, when pyruvate formation exceeds pyruvate oxidation, including in a state of low mitochondrial oxidative capacity [8].

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