# Brown Adipose Tissue undergoes pathological perturbations and shapes C2C12 myoblast homeostasis in the SOD1-G93A mouse model of Amyotrophic Lateral Sclerosis

## TL;DR

This study shows that brown fat in ALS mice is dysfunctional and releases harmful particles that impair muscle cell health.

## Contribution

The study reveals novel pathological changes in brown adipose tissue and its extracellular vesicles in an ALS mouse model.

## Key findings

- BAT from SOD1-G93A mice shows mitochondrial dysfunction and impaired differentiation.
- BAT-derived EVs from ALS mice alter size and cargo and negatively affect muscle cell homeostasis.
- EVs induce atrophy in C2C12-derived myotubes, linking BAT dysfunction to muscle decline.

## Abstract

Amyotrophic lateral sclerosis (ALS) is a
progressive neurodegenerative disease characterized by the selective loss of
motor neurons. The contribution of peripheral organs remains incompletely
understood. We focused our attention on brown adipose tissue (BAT) and its
secreted extracellular vesicles (EVs) given their role in regulating systemic
energy balance. In this study, we employed a multi-omics approach, including RNA
sequencing (GEO identifier GSE273052) and proteomics (ProteomeXchange identifier
PXD054147), to investigate the alterations in BAT and its EVs in the SOD1-G93A
mouse model of ALS. Our results revealed consistent changes in the proteomic and
transcriptomic profiles of BAT from SOD1-G93A mice, highlighting alterations
such as mitochondrial dysfunction and impaired differentiation capacity.
Specifically, primary brown adipocytes (PBAs) from SOD1-G93A mice exhibited
differentiation impairment, respiratory defects, and alterations in
mitochondrial dynamics. Furthermore, the BAT-derived EVs from SOD1-G93A mice
displayed distinct changes in size distribution and cargo content. In parallel,
such EVs negatively impacted the differentiation and homeostasis of C2C12 murine
myoblasts, as well as induced atrophy in C2C12-derived myotubes. These findings
suggest that BAT undergoes pathological perturbations in ALS mouse model and
could impact on skeletal muscle homeostasis through the secretion of
dysfunctional EVs.