Tired of Being Tired?
Skeletal muscle mitochondrial impairment in patients with newly diagnosed multiple sclerosis revealed
by ¹H/³¹P magnetic resonance spectroscopy
Kollar, B., Penesova, A., Klepochova, R., Siarnik, P., Vlcek, M., Krumpolec, P., Mosna, L., Imrich, R., Turcani, P., Radikova, Z. & Krssak, M.
Scientific Reports, 2026 Jun 11;16(1):26621, https://doi.org/10.1038/s41598-026-54705-8
Introduction:
Intractable fatigue can be a disabling feature of MS. It may occur early in the disease and can be severe enough to prevent normal daily activities. MS-related fatigue persists despite adequate rest, is not related to a particular physical disability, and can be only moderately ameliorated with drugs such as modafinil and armodafinil.
The causes of MS-related fatigue are uncertain though multiple factors have been implicated. Several studies suggest that the fatigue is the result of disconnects between various brain regions. Other studies implicate abnormalities in central nervous system metabolism, of altered glucose metabolism, of impaired sleep, and because of toxic proteins (cytokines) secreted by inflammatory cells in the both central nervous system and systemically .
The paper discussed in this blog provides important new insights into previous observations suggesting metabolic abnormalities of skeletal muscles in persons with MS, a dysfunction that could play a major role in contributing to disabling fatigue.
Numerous researchers have described metabolic muscle abnormalities MS, but a key unanswered question is whether these changes are part of the MS disease process or are a secondary phenomenon, resulting from the heightened systemic inflammation that occurs with this illness. The above paper’s authors finding of muscle abnormalities in newly diagnosed persons with MS with minimal disability and no previous disease-modifying therapy, strongly suggests that metabolic muscle abnormalities may be a primary phenomenon of MS, not a secondary consequence.
The nature of the muscle abnormalities implicates a dysfunction of structures within muscle cells called mitochondria. Mitochondria are small organelles present in all human cells. They are the “energy factories” of cells, responsible for producing components essential for normal cell metabolism. Mitochondria are also involved in multiple other essential functions, such as control of inflammation. Additional functions are detailed in multiple articles. As an interesting aside, mitochondria are believed to have evolved from bacteria, their presence allowing the development of multicellular organisms
Key Points:
1. The researchers used a technique called “high-strength (7 Tesla) magnetic resonance spectroscopy”, or MRS. The technique allows the precise measurement of components involved in cell metabolism. They studied these compounds using radioactively labeled hydrogen (1H-MRS) and radioactively labeled phosphorous (31P-MRS) as markers.
2. Measurements were obtained from study subjects’ calf muscle (gastrocnemius) at rest and after 6 minutes of exercise.
3. Study subjects were 9 individuals with recent onset, untreated multiple sclerosis. All had minimal disability (EDSS <2). Nine healthy control individuals were matched for body weight, height and levels of previous daily activity.
4. Using MRS, metabolic compounds produced by muscles, such as phosphocreatine (Pcr), acetyl carnitine, and carnosine were compared in persons with MS to controls.
5. Systemic metabolism, using oral glucose tolerance testing, measuring insulin levels, and concentrations of glucagon-like peptide-1 (GLP-1) were also studied in blood from both groups of study subjects. GLP-1 is an incretin. Incretins are gut hormones, released after eating, that lower blood sugar by stimulating the pancreas to release more insulin.
6. There were no differences in any of the systemic metabolites measured in the two groups (plasma glucose, insulin, or glucose-dependent insulinotropic polypeptide concentration profiles).
7. However, the GLP-1 response to oral glucose load was significantly lower in persons with MS, as was average GLP-1 concentrations in persons with MS.
8. Static or resting 1H-MRS testing of muscle revealed multiple metabolic abnormalities. Persons with MS had significantly lower concentration of carnosine in the gastrocnemius muscle (p = 0.044), reaching about 66% of the level in controls. Higher carnosine levels were associated with greater phosphocreatine (PCr) drop only in persons with MS (r = 0.740, p = 0.036).
9. Static or resting 31P-MRS measurements in persons with MS showed higher phosphodiester levels associated with higher insulin levels (r = 0.741, p = 0.022) and a higher resting pH (r = 0.822, p = 0.007).
10. During dynamic (exercise) 31P-MRS measurements, pre-exercise inorganic phosphate (Pi) measured at rest was significantly higher in persons with MS (p = 0.012). The corresponding PCr/Pi ratio at rest was lower, but without statistical significance (p = 0.056). The researchers said these findings suggested “subtle alterations in muscle energy metabolism.” In persons with MS higher PCr levels at rest, during exercise, and during recovery were associated with higher GLP-1 levels (r = 0.834, p = 0.005; r = 0.681, p = 0.043, and r = 0.730, p = 0.026, respectively). No such associations were observed in controls.
11. Phosphocreatine (PCr) is a source of energy for muscles and is used during muscle contraction. In persons with MS the time constant of PCr recovery after exercise was longer (40.7 ± 7.5 s), taking about 135% longer than in controls (30.2 ± 9.9 s, p = 0.031), and indicating slower post-exercise PCr resynthesis. In controls, PCr recovery time increased with increasing insulin concentrations (r = 0.843, p = 0.009) and also noted using a model of homeostatic insulin resistance (r = 0.774, p = 0.024). This relationship was absent in persons with MS.
Discussion:
MS related fatigue is almost certainly the result of multiple factors. The findings reported in this paper, of altered skeletal muscle metabolism occurring very early in minimally disabled, untreated persons with MS suggests such metabolic abnormalities are primary to the disease and have the potential to contribute substantively to disease-related fatigue. While their findings do not unequivocally prove that metabolic muscle abnormalities are a primary abnormality in MS, they strongly imply that, in the authors’ words, “a decreased glucose-stimulated GLP-1 response in newly diagnosed, treatment-naïve persons with MS suggests that alterations in incretin physiology may be present at disease onset, potentially preceding overt metabolic dysfunction and contributing to systemic metabolic dysregulation in MS”.
Static or resting 1H-MRS revealed lower carnosine levels in the gastrocnemius muscle of persons with MS compared to controls. Carnosine has multiple functions. It regulates muscle pH during exercise, modulates calcium metabolism, and has antioxidant properties. These functions maintain muscle stability and delay muscle fatigue after intense physical activity. While age, sex and lack of physical activity can affect carnosine levels, these factors were controlled in this study, suggesting carnosine deficiency in persons with MS is not a secondary phenomenon.
Acetylcarnitine plays a major role in skeletal muscle mitochondrial metabolism. It increases insulin sensitivity and allows muscle to better utilize energy-producing compounds such as acetyl-CoA. Reduced acetylcarnitine is associated with insulin resistance, impaired mitochondrial function, and lower physical activity. Can these metabolic deficiencies be alleviated with supplements? Carnosine and acetylcarnitine supplements have had limited testing as treatments for MS with inconsistent results. Their intramuscular content may thus be determined by a primary metabolic irregularity rather than dietary insufficiency, again suggesting an inability of MS muscle to maintain metabolic stability.
Slower PCr recovery after exercise in persons with MS is an indicator of impaired and reduced mitochondrial capacity in skeletal muscle. These changes were not seen in controls, providing additional support that disease-specific factors such as intrinsic mitochondrial dysfunction play an important role in muscle energy metabolism in mild, untreated, recently diagnosed persons with MS.
Glucagon like peptide-1, GLP-1, a gut-secreted, food-induced hormone or incretin, has achieved iconic status as a treatment for multiple metabolic abnormalities, such as Type II diabetes and obesity. Positive correlation of GLP-1 responses and PCr levels during the exercising studies in persons with MS in this paper may reflect a disease-specific link between skeletal muscle energetics and incretin secretion. There is some experimental evidence that GLP-1 may influence skeletal muscle mitochondrial biology. Altered GLP-1 secretion may contribute to differences in mitochondrial energy handling in skeletal muscle in persons with MS, particularly under conditions of increased energetic demand.
A recent review summarized the results of administering GLP-1 agonists in animal models of MS (e.g. experimental autoimmune encephalomyelitis) and in persons with MS. While GLP-1 agonists showed beneficial effects in animal studies, the human studies did not. However, the human studies had substantive flaws, such as no control groups, limited clinical evaluations, no randomization, selection bias and using subjects already on high-efficacy disease-modifying therapies. As expected, GLP-1 agonists resulted in weight loss in persons with MS, were well tolerated, but with no effect on neurologic function, either for better or worse. The authors conclude that, based on currently available data, use of GLP-1 agonists as a treatment for MS is not established. However, the finding of skeletal muscle metabolic abnormalities with impaired recovery from exercise being possible substantive contributors to often-disabling fatigue of the disease, provides a powerful incentive to further study potential treatments, such GLP-1 agonists, in better designed, more controlled studies. If successful, an entirely new approach to treatment of disabling MS fatigue would be achieved.
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