Nerve damage induced skeletal muscle atrophy is associated with increased accumulation of intramuscular glucose and polyol pathway intermediates

Henning Tim Langer,Stefan Kempa,Shoaib Afzal,Simone Spuler

doi:10.1038/s41598-020-58213-1

Abstract

Perturbations in skeletal muscle metabolism have been reported for a variety of neuromuscular diseases. However, the role of metabolism after constriction injury to a nerve and the associated muscle atrophy is unclear. We have analyzed rat tibialis anterior (TA) four weeks after unilateral constriction injury to the sciatic nerve (DMG) and in the contralateral control leg (CTRL) (n = 7) to investigate changes of the metabolome, immunohistochemistry and protein levels. Untargeted metabolomics identified 79 polar metabolites, 27 of which were significantly altered in DMG compared to CTRL. Glucose concentrations were increased 2.6-fold in DMG, while glucose 6-phosphate (G6-P) was unchanged. Intermediates of the polyol pathway were increased in DMG, particularly fructose (1.7-fold). GLUT4 localization was scattered as opposed to clearly at the sarcolemma. Despite the altered localization, we found GLUT4 protein levels to be increased 7.8-fold while GLUT1 was decreased 1.7-fold in nerve damaged TA. PFK1 and GS levels were both decreased 2.1-fold, indicating an inability of glycolysis and glycogen synthesis to process glucose at sufficient rates. In conclusion, chronic nerve constriction causes increased GLUT4 levels in conjunction with decreased glycolytic activity and glycogen storage in skeletal muscle, resulting in accumulation of intramuscular glucose and polyol pathway intermediates.

Highlights

Perturbations in skeletal muscle metabolism have been reported for a variety of neuromuscular diseases
The main purpose of this study was to investigate the changes occurring to skeletal muscle metabolism with chronic nerve constriction injury and relate them back to findings in nerve transection and other neuromuscular diseases
We found that chronic constriction injury of the sciatic nerve in rats results in increased intramuscular glucose and polyol pathway intermediate concentrations

Summary

Introduction

Perturbations in skeletal muscle metabolism have been reported for a variety of neuromuscular diseases. We have analyzed rat tibialis anterior (TA) four weeks after unilateral constriction injury to the sciatic nerve (DMG) and in the contralateral control leg (CTRL) (n = 7) to investigate changes of the metabolome, immunohistochemistry and protein levels. We found GLUT4 protein levels to be increased 7.8-fold while GLUT1 was decreased 1.7fold in nerve damaged TA. Chronic nerve constriction causes increased GLUT4 levels in conjunction with decreased glycolytic activity and glycogen storage in skeletal muscle, resulting in accumulation of intramuscular glucose and polyol pathway intermediates. Research in respect to nerve damage and glucose metabolism has reported that denervation is followed by insulin resistance, reduced glucose transport into the muscle, less glucose abundance and transiently decreased GLUT4 levels[7,8,9]. We utilized a combination of untargeted metabolomics, immunohistochemistry and western blotting to examine alterations and potentially underlying mechanisms

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Conclusion