RAGE Cytosolic Partner Diaph1 Does Not Play an Essential Role in Diabetic Peripheral Neuropathy Progression

TL;DR

Deleting Diaph1 in mice does not stop diabetic peripheral neuropathy, but it partially improves some nerve-related issues.

Contribution

This study is the first to rigorously test Diaph1's role in diabetic peripheral neuropathy using a knockout mouse model.

Findings

Deleting Diaph1 does not prevent diabetes-induced loss of β-actin in sciatic nerve fibers.

Diaph1 deletion partially rescues axonal and fiber diameter abnormalities in diabetic mice.

Nerve conduction defects caused by hyperglycemia remain unimproved despite Diaph1 deletion.

Abstract

What are the main findings?

Global deletion of Diaph1 disrupts beta-actin polymerization in the sciatic nerve during type 1 diabetes.

We observed decreased nerve conduction velocity and abnormalities in sciatic nerve morphometry in diabetic Diaph1 knockout diabetic mice.

What is the implication of the main finding?

Deletion of Diaph1 is insufficient to halt the progression of diabetic peripheral neuropathy in mice.

However, we cannot unequivocally rule out that Diaph1 is an important switch role in the RAGE pathway and diabetic peripheral neuropathy.

Receptor for advanced glycation end-products (RAGE) activation by hyperglycemia-induced AGE (advanced glycation end-products) accumulation is likely to play a crucial role in the development of complications such as diabetic peripheral neuropathy (DPN). RAGE signaling is mediated via its cytosolic tail. Through its cytosolic tail, RAGE recruits diaphanous-related formin 1 (Diaph1), a protein involved in actin filament organization. Disruption of RAGE–Diaph1 interactions using small molecules alleviates diabetic complications in mice; however, the role of Diaph1 in DPN progression has not been rigorously tested. In this study, we employed a Diaph1 knockout mouse (DKO) to investigate the role of Diaph1 in DPN progression. Herein, we demonstrate that, at the systemic level, CRISPR deletion of Diaph1 fails to ameliorate diabetes-induced weight loss in mice. Within the sciatic nerve (SCN), the lack of Diaph1 failed to prevent hyperglycemia-induced loss of β-actin in the nerve fibers. At a morphological level, the lack of Diaph1 leads to a partial rescue in DPN. While we observed improvements in axonal and fiber diameters in diabetic DKO mice, the g-ratio (an indicator of myelination) and myelin invaginations displayed incomplete rescue. Furthermore, the lack of Diaph1 failed to rescue motor or sensory nerve conduction defects resulting from hyperglycemia over 6 months. Overall, our data thus indicate that the complete loss of Diaph1 is insufficient to halt the progression of DPN. However, across a range of parameters including blood glucose levels, body weight measurements, axon and fiber diameters, and nerve conduction velocity, DKO diabetic mice show improvement when compared to wild-type diabetic mice.

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