# Insights into intramuscular adipose–muscle signaling in the diabetic lower extremity

## TL;DR

This study explores how intramuscular fat affects muscle cell development in diabetes, finding that diabetic muscle cells respond poorly to signals from fat tissue.

## Contribution

The study reveals that diabetic myoblasts are uniquely sensitive to adipose-derived signals, impacting muscle regeneration.

## Key findings

- IMAT from diabetic individuals showed reduced inflammatory pathways compared to subcutaneous fat.
- Diabetic myoblasts had lower fusion rates when exposed to conditioned media from any adipose source.
- IMAT secreted factors may hinder muscle regeneration in diabetes due to myoblast sensitivity.

## Abstract

Insights into Intramuscular Adipose–Muscle Signaling in the Diabetic Lower Extremity. This study compared biopsies of intramuscular adipose tissue (IMAT) and subcutaneous adipose tissue (SQ) using transcriptional profiling, histological analyses and cell culture models to better understand the effect of IMAT on myogenesis (green arrow).

•Excess IMAT could impair myoblast differentiation through paracrine signaling.•Transcriptional differences between IMAT and SQ suggest unique signaling by IMAT.•Both IMAT and SQ conditioned media impaired diabetic myoblast differentiation.•Sensitivity of myoblasts to adipokines may drive impaired regeneration in diabetes.

Excess IMAT could impair myoblast differentiation through paracrine signaling.

Transcriptional differences between IMAT and SQ suggest unique signaling by IMAT.

Both IMAT and SQ conditioned media impaired diabetic myoblast differentiation.

Sensitivity of myoblasts to adipokines may drive impaired regeneration in diabetes.

Intramuscular adipose tissue (IMAT) has been proposed to directly contribute to myofiber dysfunction through paracrine signaling. The impacts of this signaling beyond contributing to myofiber insulin resistance are largely unknown. This study aims to explore the human IMAT transcriptome, with a focus on its potential role in myoblast fusion deficits in advanced muscle pathology. Using a within-subjects design, we compared IMAT to subcutaneous (SQ) fat in individuals with and without diabetes undergoing below-knee amputation. We hypothesized that IMAT from the diabetic group would exhibit a pro-inflammatory profile, similar to diabetic SQ, and that inflammatory secreted factors from IMAT progenitors would impair cultured myoblast fusion. Instead, we found that the IMAT transcriptome from the diabetic group exhibited reduced enrichment of inflammatory pathways compared with SQ and less transcriptional evidence for immune cell infiltration. While IMAT featured a mostly anti-myogenic transcriptional profile for secreted cytokines, media conditioned by IMAT progenitors did not uniquely impair fusion of cultured myoblasts compared with SQ. Surprisingly, the diabetic status of the myoblast donor predicted myoblast fusion, with reduced fusion rates in diabetic myoblasts exposed to conditioned media from all adipose sources. This suggests that IMAT-myoblast signaling may be detrimental to regeneration in diabetes, but that the effect is driven in part by an intrinsic difference in diabetic myoblasts’ sensitivity to IMAT secreted factors. This emphasizes the insight that can be gained from disease-state matched and mismatched culture models and highlights the need to better understand how diabetes impacts myoblasts and their interaction with the disease environment.