Endocrine-metabolic decoupling drives stress vulnerability in dystrophin deficiency

ABSTRACT: Skeletal muscle orchestrates systemic metabolism, dynamically coordinating glucose uptake and fuel use to match energy demand. In Duchenne muscular dystrophy, loss of dystrophin derails this control, exposing a hidden metabolic weakness. In the mdx mouse, we show that physiological stress exposes a primary failure in insulin-stress axis integration: unchecked glucocorticoid signalling outpaces insulin secretion, driving systemic hyperglycaemia despite preserved muscle insulin sensitivity. These data support multi-tissue dystrophinopathy driving endocrine-metabolic decoupling. Skeletal muscle glycogen accumulates excessively and resists mobilisation under stress. The heart maintains high glucose uptake, whereas the brain remains glucose-limited, defining tissue-specific vulnerabilities. Acute insulin supplementation normalises systemic glucose uptake and rescues stress-induced behavioural deficits. Likewise, empagliflozin-mediated glucose offloading stabilises blood glucose and enhances muscle function to levels comparable with standard care prednisolone. These findings identify endocrine-metabolic decoupling as a central driver of metabolic fragility in TMT, correctable though insulin restoration or targeted glucose redirection.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Muscle

SUBMITTER: Joel Steele  

LAB HEAD: Alan Hayes

PROVIDER: PXD076307 | Pride | 2026-10-20

REPOSITORIES: Pride