Hyperglycemia-induced metabolic rewiring is associated with skeletal muscle loss in a fructose-streptozotocin-induced diabetic rat model.

Aims

This study investigated the impact of hyperglycemia on systemic and skeletal muscle metabolite profiles.

Methods

Serum and gastrocnemius metabolites of fructose-fed, streptozotocin-injected rats (T2D) were analyzed by 1H NMR and related to markers of energy metabolism and mitochondrial remodeling.

Results

T2D rats exhibited hyperglycemia and impaired insulin secretion without obesity or dyslipidemia. Hyperglycemia induced a generalized catabolic state, reflected by reduced body weight and relative gastrocnemius mass. T2D rats presented increased phosphorylated AMP-activated protein kinase (pAMPK) and peroxisome proliferator-activated receptor alpha (PPARα) muscle levels and pAMPK/AMPK ratio, which correlated with muscle mass loss, indicating AMPK signaling and fatty acid oxidation activation. 1H NMR results suggested muscle proteolysis, with elevated serum levels of isoleucine, alanine, glycine, and threonine in T2D rats. Reduced muscle levels of all three branched-chain amino acids (BCAAs) were also detected in T2D rats, suggesting enhanced BCAA oxidation/impaired uptake. T2D rats also exhibited elevated 3-hydroxybutyrate and acetate serum levels. No changes were observed in glucose, glucose transporter 4 (GLUT4), and 6-phosphofructokinase muscle type (PFKM) muscle levels, or ATP synthase activity.

Conclusions

These findings demonstrate an association between hyperglycemia and muscle loss, with muscle loss being associated with metabolic reprogramming toward the preferential utilization of non-glucose substrates, possibly to preserve energy homeostasis at the expense of protein maintenance.