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Publications

Journal Article Ahead of print

PubMed: 42192415 DOI: 10.1186/s12933-026-03190-4

Exerkine dysregulation links visceral adiposity to skeletal muscle impairment in end-stage heart failure with reduced ejection fraction: proteomic evidence for a cardio-adipose-muscle axis.

Cardiovasc Diabetol

Authors: Marta Załęska-Kocięcka, Maciej Mazuruk, Karolina Szcześniak, Piotr Łaba, Marta Kacperska, Łukasz Nogajski, Maksymilian Nowakowski, Maciej Mączewski, Hanna Czerwińska, Miłosz Rosa, Piotr Olbryś, Aleksandra Mączyńska, Jarosław Kuriata, Piotr Kołsut, Zuzanna Wojdyńska, Ilona Michałowska, Aleksandra Paterek, Przemysław Błyszczuk, Przemysław Leszek, Michał Mączewski

Affiliations

  • Heart Failure and Transplantology Department, Mechanical Circulatory Support and Transplant Department, National Institute of Cardiology, Warsaw, Poland.
  • Heart Failure and Transplantology Department, Mechanical Circulatory Support and Transplant Department, National Institute of Cardiology, Warsaw, Poland.
  • Department of Clinical Physiology, Centre of Postgraduate Medical Education, Warsaw, Poland.
  • Student's Cardiovascular Scientific Club "Kardioplegia", Medical University of Warsaw, Warsaw, Poland.
  • Department of Cardiac Surgery, National Institute of Cardiology, Warsaw, Poland.
  • Department of Radiology, National Institute of Cardiology, Warsaw, Poland.
  • Department of Clinical Immunology, Jagiellonian University Medical College, Cracow, Poland.
  • Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

Abstract

BACKGROUND

Heart failure with reduced ejection fraction (HFrEF) is associated with profound alterations in body composition, skeletal muscle dysfunction, and impaired exercise capacity. Exerkines representing exercise-responsive signaling molecules released by skeletal muscle, adipose tissue, and other organs may mediate systemic metabolic communication between tissues. However, their role in advanced HFrEF and their relationship with adiposity and skeletal muscle characteristics remain poorly understood.

METHODS

We studied 73 patients with end-stage HFrEF and 16 healthy controls. Body composition was assessed using computed tomography, including visceral (VAT), subcutaneous (SAT), and epicardial adipose tissue (EAT), as well as skeletal muscle quantity (psoas muscle index, PMI) and quality (psoas muscle density, PMD). Functional performance was evaluated using handgrip strength (HGT) and the 6-min walk test (6MWT). Circulating exerkines were quantified using the Olink technology. Associations between proteins and clinical variables were assessed using age- and creatinine-adjusted linear models with false discovery rate correction.

RESULTS

Among patients with HFrEF, 36% were obese and 38% exhibited central obesity independent of BMI. Muscle strength and muscle quality were strongly associated with functional capacity. VAT correlated with muscle mass but not with muscle quality or performance. Compared with controls, HFrEF patients demonstrated elevated inflammatory and metabolic stress-related exerkines including CXCL8, CCL2, IL-6, TNF, IL-15, GDF15, FGF21, ANGPTL4, CTSB, DCN, and resistin. In contrast, proteins associated with muscle integrity and regenerative signaling (myostatin, BDNF, IL-7, SPARC) were significantly reduced. In HFrEF patients leptin strongly correlated with adiposity measures. Metabolic stress mediators (GDF15, IL-15, FGF21, CTSB) were inversely associated with muscle quality and functional performance, whereas myostatin positively correlated with muscle quality, strength, and exercise capacity. BDNF was inversely associated with frailty.

CONCLUSIONS

Advanced HFrEF is characterized by a dysregulated exerkine network linking adiposity, skeletal muscle quality, and functional performance. Four biologically coherent axes were identified: a leptin-driven adiposity axis, a metabolic stress-muscle quality axis, a myostatin-related muscle function axis, and a neurotrophic frailty axis. These findings support the presence of a systemic cardio-adipose-muscle signaling network in end-stage HFrEF and identify candidate molecular mediators of sarcopenia and functional decline.

MeSH

Exercise, Muscles, Psoas Muscles, Leptin, Heart Failure, Heart, Stress, Physiological, Adiposity, Heart Failure, Systolic, Myostatin, Muscle, Skeletal, Frailty, Tissues, Diabetes Complications, Adipose Tissue