Skeletal muscle mitochondrial impairment in patients with newly diagnosed multiple sclerosis revealed by ¹H/³¹P magnetic resonance spectroscopy

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Abstract Mitochondrial dysfunction is implicated in the pathophysiology of multiple sclerosis (MS) and may contribute to its fatigue and muscle weakness. Whether skeletal muscle metabolic changes are present at disease onset is unclear. In this observational matched case-control study we investigated muscle metabolism and its relation to systemic metabolic measures in newly diagnosed, treatment-naïve patients with MS (PwMS) and matched healthy controls. Gastrocnemius metabolism was assessed using static and dynamic 7 T 1 H/ 31 P magnetic resonance spectroscopy (MRS), measuring energy metabolites, membrane-related compounds, and post-exercise phosphocreatine (PCr) recovery. Systemic metabolism was assessed by oral glucose tolerance test (OGTT) measuring glucose, insulin, and GLP-1. Static MRS revealed lower carnosine ( p = 0.044) and a trend toward lower acetylcarnitine in PwMS. Dynamic ³¹P-MRS showed elevated pre-exercise inorganic phosphate (Pi; p = 0.012), trend toward reduced PCr/Pi ratio, and prolonged PCr recovery ( p = 0.031) in PwMS. PwMS also had reduced GLP-1 response during OGTT ( p = 0.032) despite preserved insulin sensitivity. Higher PCr levels were associated with greater GLP-1 response in PwMS only; longer PCr recovery was associated with insulin resistance parameters in controls only. Newly diagnosed MS is associated with skeletal muscle mitochondrial impairment during energetic stress, despite largely preserved systemic metabolic status. Altered metabolites, delayed recovery, and association with reduced GLP-1 response suggest impaired muscle bioenergetics and altered systemic metabolic regulation present at disease onset. Targeting mitochondrial and metabolic pathways offers therapeutic potential in early MS. Trial registration number: ClinicalTrials.gov: NCT03052595, date of registration: 14th Feb 2017.

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