Metabolic Disturbance in Patients with Muscular Dystrophy and Reflection of Altered Enzyme Activity in Dystrophic Muscle: One Critical View

Abstract

Muscular dystrophies are inherited myogenic diseases and considered by progressive muscle wasting and weakness with variable distribution and severity. The essential characteristics of muscular dystrophies are selective involvement, significant wasting and weakness of muscles. The most common and frequent types of muscular dystrophies are Duchenne Muscular Dystrophy (DMD), Becker Muscular Dystrophy (BMD), Facioscapulohumeral Dystrophy (FSHD) and Limb Girdle Muscular Dystrophy (LGMD). Metabolic disturbance is observed in muscular dystrophy patients (DMD, BMD, FSHD and LGMD-2B). Alteration in the level of metabolites (BCAA, Glu/ Gln, Ace, alanine, glucose, histidine, propionate, tyrosine and fumarate) in dystrophic muscle reflects the alteration in the activity of enzymes. Collectively, these observations propose that there is alteration in the rate of glycolysis, TCA cycle, fatty acid oxidation, gluconeogenesis pathway and protein metabolism (catabolism & anabolism) in the muscular dystrophy patients. Metabolic disturbance, further provide the explanation about the pathophysiology of muscular dystrophy.

Loss of full-length dystrophin expression results in major cell-autonomous abnormalities in proliferating myoblasts

“…Significant enzymatic and downstream metabolic changes have been previously observed in DMD ( Aoyagi et al, 1983 ; Dreyfus et al, 1956 ; Ragusa et al, 1997 ; Srivastava et al, 2020 ). In order to fully take into account both enzymatic and metabolic activity within DMD myoblasts, a condition-specific and enzyme-constrained human metabolic model was constructed to characterise such changes at the genome-scale.…”

“…A significant upregulation in glycolytic enzymes, including Hexokinase-1 and Pyruvate Kinase M2, was observed in dysfunctional muscles, indicating the increased glycolytic activity ( Pant et al, 2015 ). The activity of individual glycolytic enzymes (such as alpha-glucan phosphorylase, phosphoglucomutase, and aldolase), creatine kinase and Adenylate kinase 1 is reduced in DMD ( Srivastava et al, 2020 ). Furthermore, the first two enzymes of the pentose phosphate pathway of glucose utilisation, glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase, have enhanced activity.…”