Is Metabolic Flexibility Altered in Multiple Sclerosis Patients?

Anja Mähler,Markus Bock,Verena Haas,Friedemann Paul,Jochen Steiniger,Michael Boschmann,Alexander U Brandt,Stephane Blanc

doi:10.1371/journal.pone.0043675

Abstract

ObjectivesMetabolic flexibility is defined as ability to adjust fuel oxidation to fuel availability. Multiple sclerosis (MS) results in reduced muscle strength and exercise intolerance. We tested the hypothesis that altered metabolic flexibility contributes to exercise intolerance in MS patients.MethodsWe studied 16 patients (all on glatiramer) and 16 matched healthy controls. Energy expenditure (EE), and carbohydrate (COX) and lipid oxidation (LOX) rates were determined by calorimetry, before and after an oral glucose load. We made measurements either at rest (canopy device) or during 40 min low-grade (0.5 W/kg) exercise (metabolic chamber). We also obtained plasma, and adipose tissue and skeletal muscle dialysate samples by microdialysis to study tissue-level metabolism under resting conditions.ResultsAt rest, fasting and postprandial plasma glucose, insulin, and free fatty acid levels did not differ between patients and controls. Fasting and postprandial COX was higher and LOX lower in patients. In adipose, fasting and postprandial dialysate glucose, lactate, and glycerol levels were higher in patients vs. controls. In muscle, fasting and postprandial dialysate metabolite levels did not differ significantly between the groups. During exercise, EE did not differ between the groups. However, COX increased sharply over 20 min in patients, without reaching a steady state, followed by an immediate decrease within the next 20 min and fell even below basal levels after exercise in patients, compared to controls.ConclusionsGlucose tolerance is not impaired in MS patients. At rest, there is no indication for metabolic inflexibility or mitochondrial dysfunction in skeletal muscle. The increased adipose tissue lipolytic activity might result from glatiramer treatment. Autonomic dysfunction might cause dysregulation of postprandial thermogenesis at rest and lipid mobilization during exercise.

Highlights

Multiple sclerosis (MS) is the most common non-traumatic autoimmune neurological disease among young adults
[4] Reduced respiratory chain complex IV activity has been observed within demyelinated axons in MS patients. [5,6] In Huntingtons disease, faulty complex I activity, as well as other deficits in muscle mitochondrial oxidative metabolism have been observed. [7,8] investigators recorded increased energy expenditure during both fasting and hyperinsulinemic-euglycemic conditions
Baseline values and postprandial profiles of plasma glucose, insulin, and free fatty acids (FFA) concentrations did not differ between the groups (Fig. 2)

Summary

Introduction

Multiple sclerosis (MS) is the most common non-traumatic autoimmune neurological disease among young adults. [1] Irreversible neuroaxonal damage results in a wide range of symptoms, including complex functional impairments such as abnormal walking mechanics, poor balance, muscle weakness, and exercise intolerance. [4] Reduced respiratory chain complex IV activity has been observed within demyelinated axons in MS patients. [5,6] In Huntingtons disease, faulty complex I activity, as well as other deficits in muscle mitochondrial oxidative metabolism have been observed. [10] A recent study reported significantly reduced complex I activity in freshly isolated mitochondria from skeletal muscle in Persian MS patients. We reasoned that a reduced metabolic flexibility might contribute to exercise intolerance above-and-beyond neural dysfunction. Impaired oxidative metabolism due to altered mitochondrial function results in increased lactate production and an elevated lactate/pyruvate ratio. Impaired oxidative metabolism due to altered mitochondrial function results in increased lactate production and an elevated lactate/pyruvate ratio. [13,14] Alternatively, an impaired function of the autonomic nervous system might impair substrate mobilization and contribute to exercise intolerance

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