Persistent Postirradiation Skeletal Muscle Protein and Insulin Sensitivity Changes in Nonhuman Primates

Area of Science:

• Endocrinology
• Radiation Biology
• Muscle Physiology

Background:

• Whole-body irradiation is linked to increased diabetes incidence in cancer survivors and animal models.
• Type 2 diabetes post-irradiation occurs without obesity, implicating skeletal muscle dysfunction.
• Skeletal muscle is crucial for glucose disposal and minute-to-minute glucose regulation.

Purpose of the Study:

• To investigate the persistent effects of whole-body irradiation on skeletal muscle insulin sensitivity.
• To identify molecular mechanisms underlying radiation-induced skeletal muscle insulin resistance.

Main Methods:

• Analysis of skeletal muscle from control and irradiated male rhesus macaques 4 years post-irradiation (6.5 Gy).
• Evaluation of basal and insulin-stimulated receptor activation in skeletal muscle.
• Proteomic analysis (shotgun proteomics, immunoblotting) to identify protein changes, including post-translational modifications like sulfenylation.
• Assessment of mitochondrial dynamics markers (fission and fusion).

Main Results:

• Irradiated skeletal muscle exhibited deficient basal and insulin-stimulated receptor activation.
• Akt2, a key insulin signaling protein, showed radiation-induced sulfenylation, indicating dysregulation.
• Proteomics revealed upregulation of mitochondrial and peroxisome-associated proteins in irradiated muscle.
• Increased markers for mitochondrial fission and fusion suggest altered mitochondrial turnover and dynamics.

Conclusions:

• Irradiated skeletal muscle demonstrates persistent insulin resistance.
• Radiation exposure leads to intracellular protein oxidation and altered mitochondrial function in muscle.
• These molecular and functional changes in skeletal muscle contribute to radiation-induced glycemic dysregulation and diabetes.