Low-frequency ultrasound reverses insulin resistance and diabetes-induced changes in the muscle transcriptome in aged mice.

The risk for developing insulin resistance and type II diabetes increases with age. Although lifestyle factors contribute to age-related insulin resistance, aging itself independently reduces insulin sensitivity, partially via an increase in inflammation and cellular senescence. Low-frequency ultrasound (LFU) has been shown to rejuvenate senescent cells and to reduce the proinflammatory senescence-associated secretory phenotype. Because diabetes is more common in aged individuals, there is an increased need to develop effective therapeutics for aged individuals with this condition. This study investigated the effects of LFU treatment on muscle function, blood glucose control, and skeletal muscle gene expression in aged, insulin-resistant, and diabetic mice. Insulin resistance was induced via a high-fat, high-sucrose (HFHS) diet, and diabetes was induced via an HFHS diet plus a low dose of streptozotocin. Insulin-resistant and diabetic mice exhibited impaired glucose metabolism and physical function, as well as an altered transcriptomic profile in skeletal muscle, indicating an increase in inflammation and an immune response. LFU treatment reversed much of the transcriptomic changes that occurred with insulin resistance and diabetes but had no effect on blood glucose control or physical function. LFU demonstrates potential as a noninvasive therapy for reducing inflammation and altering immune cell function in skeletal muscle in insulin-resistant and diabetic populations. This study introduces low-frequency ultrasound (LFU) as a novel, noninvasive therapy that attenuates insulin resistance- and diabetes-induced transcriptional changes in aged skeletal muscle. LFU primarily reduced inflammatory and immune-related gene expression, potentially by promoting a shift toward an anti-inflammatory (M2) macrophage profile. These findings suggest that LFU may target underlying inflammatory mechanisms of insulin resistance and diabetes in aging muscle.