How does multiple sclerosis affect lactic acid production or utilization?

Multiple Sclerosis and Lactic Acid Metabolism

Multiple sclerosis (MS) affects lactic acid metabolism by causing elevated resting blood lactate levels, reduced maximal lactate production during exercise, and alterations in the expression of glucose-metabolizing enzymes in MS lesions, reflecting mitochondrial dysfunction and compensatory metabolic shifts. 1

Pathophysiological Changes in Lactic Acid Metabolism

Elevated Resting Lactate Levels

• Blood lactate concentration at rest is elevated in people with MS compared to healthy controls, suggesting altered baseline energy metabolism 1
• Cerebrospinal fluid (CSF) concentrations of lactate and other metabolites of extra-mitochondrial glucose metabolism are significantly increased in MS patients, particularly in those with secondary progressive MS 2
• These elevated levels correlate with disease progression and increasing disability as measured by the Expanded Disability Status Scale (EDSS) 2

Mitochondrial Dysfunction

• MS is characterized by impaired mitochondrial function, which leads to increased reliance on extra-mitochondrial glucose metabolism and consequently higher lactate production 2
• The activity of key mitochondrial enzymes involved in carbohydrate metabolism (lactate dehydrogenase, LDH) is reduced in most MS patients, indicating decompensation of mitochondrial function 3
• Reduced expression and production capacity of mitochondrial α-ketoglutarate dehydrogenase (αKGDH) has been observed in demyelinated axons, correlating with signs of axonal dysfunction 4

Exercise-Related Lactate Changes

• Maximum lactate production during high-intensity exercise is lower in people with MS compared to healthy controls 1
• Patients with higher disability scores (EDSS) show even lower maximal lactate production during exercise compared to those with lower disability scores 1
• This reduced capacity to produce lactate during maximal exercise may reflect impaired energy metabolism and reduced exercise capacity 1

Metabolic Shifts in MS Lesions

Active MS Lesions

• Expression levels of both glycolytic enzymes and enzymes involved in the tricarboxylic acid (TCA) cycle are upregulated in active MS lesions 4
• This likely represents an attempt to compensate for increased energy demands in inflammatory lesions 4

Inactive MS Lesions

• In inactive MS lesions, glycolytic enzymes remain upregulated while TCA cycle enzymes are not increased 4
• Astrocytes in inactive lesions show increased expression of lactate-producing enzymes 4
• Axons in these lesions predominantly express lactate-catabolizing enzymes 4
• This pattern suggests an enhanced astrocyte-axon lactate shuttle, which may be crucial for the survival of demyelinated axons 4

Clinical Implications

Diagnostic Potential

• Abnormal lactic dehydrogenase (LDH) isoenzyme patterns in cerebrospinal fluid have been observed in MS patients, with higher-than-normal levels of LDH-2, LDH-3, and LDH-5 5
• These altered patterns may have diagnostic potential as biomarkers for MS, though further investigation is warranted 5

Therapeutic Considerations

• The evidence of mitochondrial dysfunction suggests that energotropic drugs like carnicetin and coenzyme Q10 (idebenone) may be beneficial for MS patients 3
• In MELAS syndrome (a mitochondrial disorder with some metabolic similarities to MS), dichloroacetate may help reduce lactic acid levels 6
• Chronic exercise interventions have shown potential to normalize lactate metabolism in MS patients by reducing submaximal lactate levels and increasing maximal lactate production capacity 1

Monitoring Disease Progression

• Blood lactate concentration could potentially serve as a biomarker for MS onset and progression 1
• CSF metabolic profiling, including lactate measurement, may be useful in clarifying the role of mitochondrial pathology in disease progression 2
• These metabolic markers could help in targeting and monitoring therapies aimed at preserving or boosting mitochondrial glucose metabolism 2

Understanding the alterations in lactic acid metabolism in MS provides insights into disease pathophysiology and may lead to novel therapeutic approaches targeting energy metabolism to slow disease progression and improve quality of life for MS patients.