# Skeletal muscle transcriptional dysregulation of genes involved in senescence is associated with prognosis in severe heart failure

## TL;DR

This study finds that genes related to aging and cell damage in skeletal muscle are linked to worse outcomes in severe heart failure patients.

## Contribution

The study identifies p53 signaling as a novel key process in skeletal muscle dysfunction in heart failure, distinguishing it from effects of physical inactivity.

## Key findings

- Network communities related to mitochondrial beta-oxidation and extracellular matrix remodeling are downregulated in heart failure patients.
- p53 signaling community, marked by CDKN1A, is upregulated and associated with worse prognosis in heart failure patients.
- Altered gene networks suggest biological aging and inactivity contribute to skeletal muscle dysfunction in heart failure.

## Abstract

The skeletal muscle hypothesis refers to a vicious cycle of successive deterioration of left ventricular function, skeletal muscle remodeling, and functional capacity in patients with heart failure. Despite extensive research, the regulatory mechanisms and their associations with clinical status and prognosis are still largely unclear.

To identify mechanisms and characterize underlying processes involved in the disease pathophysiology, we performed RNA sequencing and network analysis using human skeletal muscle samples from 58 patients with severe symptomatic heart failure. A co-expression network with communities involved in established biological processes within human skeletal muscle was identified and validated in two independent cohorts.

Here, we show network communities associated with mitochondrial beta-oxidation, extracellular matrix remodeling, oxidative phosphorylation, and contractile elements with lower expression in heart failure patients than in age-matched controls. Based on the strong correlation with clinical features and prognosis, extracellular matrix remodeling, mitochondrial beta-oxidation, and p53 signalling communities are identified as key underlying processes. The former two communities are highly enriched with genes regulated by physical (in)activity, i.e., bed rest and exercise, and associated weakly with prognosis. Community related to p53 signalling, with CDKN1A as a key regulator, is increased in heart failure patients relative to age-matched controls and associated with worse prognosis.

The current work differentiates previously proposed factors underlying heart failure-induced skeletal muscle dysfunction, emphasizing the p53 signalling community and importance of biological age in this process. The distinct association with clinical status and prognosis furthermore supports pathophysiological significance and clinical potential of this community.

Rullman et al. explore skeletal muscle gene-expression in patients with severe heart failure. They identify upregulation of p53 signaling, a process linked to aging and cell damage to be associated with mortality, highlighting the need to separate inactivity effects from disease-specific changes and cell-cycle control as a disease mechanism.

Heart failure patients suffer from muscle weakness and reduced physical activity, symptoms that worsen with the disease progression. Although extensively studied, biological mechanisms behind it remain largely unclear. Here, we analysed skeletal muscle samples from patients with severe heart failure using gene-expression-based approach where transcripts with similar expression are grouped together into networks. We identified muscle processes related to energy metabolism and tissue repair to be altered in these patients, likely in part due to their physical inactivity. Importantly, we identified increased expression of genes linked to p53 signalling, process associated with aging and cell damage, which was also strongly related to patient outcomes. Our results distinguish and highlight the need to separate the negative effects of physical inactivity from disease-specific changes, which is essential for discovering new treatment targets.