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

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. Although some underlying processes have been characterized, the regulatory mechanisms and their associations with clinical status and prognosis are still largely unclear. To identify mechanisms and characterize plausible key processes involved in the disease pathophysiology, we performed RNA sequencing and network analysis using human skeletal muscle samples from 66 patients with severe symptomatic heart failure (HFrEF; NYHA III-IV, left ventricular ejection fraction ≤ 30). A co-expression network consisting of 14 communities, involved in well-established biological processes within human skeletal muscle was identified and validated in two independent cohorts. Network communities related to mitochondrial beta-oxidation, extracellular matrix remodeling, oxidative phosphorylation, and contractile elements were shown to have lower expression in HFrEF patients compared with age-matched controls. This is consistent with the known muscle phenotype in patients with HRrEF. Based on the strong correlation with clinical features and prognosis, extracellular matrix remodeling, mitochondrial beta-oxidation, and p53 signaling communities were identified as key processes. The former two communities were highly enriched with genes regulated by physical (in)activity, i.e., bed rest and exercise, and weak association with prognosis. Community related to p53 signaling, with CDKN1A as a key regulator, was increased in HFrEF patients compared to age-matched controls and associated with worse prognosis. The current work differentiates previously proposed factors underlying heart failure-induced skeletal muscle dysfunction, emphasizes the p53 signaling 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 the p53 signaling community.