Effect of Insulin on the Phosphoproteome of Skeletal Muscles in Normal Conditions and With Insulin Resistance

The skeletal muscles are the main site of insulin-dependent glucose uptake, and the development of insulin resistance in skeletal muscles is the main factor in the progression of insulin resistance in the whole organism. This disorder is associated with defects in the canonical insulin cascade regulating glucose uptake; however, the specific molecular mechanisms are still debatable. Global mass spectrometry-based phosphoproteomic analysis appears to be an optimal approach to studying complex signaling networks. The review summarizes data from phosphoproteomic studies investigating changes in intracellular signaling in skeletal muscles upon insulin stimulation under normal conditions and insulin resistance. In vitro and in vivo studies have shown that insulin stimulation/food intake causes large-scale changes in the phosphoproteome (hundreds of phosphosites). These changes affect not only the canonical insulin cascades but also other signaling pathways and proteins with different functions (enzymes of carbohydrate and fat metabolism, sarcomeric and mitochondrial proteins, transcription factors, chaperones, etc.) and cause transcriptomic changes. Insulin resistance impairs the phosphoproteomic response to insulin; however, these changes only slightly affect the canonical insulin cascade regulating glucose uptake. The causes of impairments in insulin-dependent glucose uptake are hypothesized to be related primarily by a combination of multiple defects in various signaling molecules that regulate glucose uptake directly or indirectly; however, they are not associated with the canonical insulin cascade.