Analysis of Skeletal Muscle Gene Expression Patterns and the Impact of Functional Capacity in Patients With Systolic Heart Failure

• Published in: Journal of cardiac failure Vol. 20; no. 6; pp. 422 - 430
• Main Authors: Forman, Daniel E., MD, Daniels, Karla M., MS, Cahalin, Lawrence P., PhD, PT, Zavin, Alexandra, BS, Allsup, Kelly, BS, Cao, Peirang, PhD, Santhanam, Mahalakshmi, PhD, Joseph, Jacob, MD, Arena, Ross, PhD, PT, Lazzari, Antonio, MD, Schulze, P. Christian, MD, PhD, Lecker, Stewart H., MD, PhD
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-06-2014
• Subjects: Aged; Cardiovascular; Cohort Studies; Cross-Sectional Studies; Exercise Test - methods; gene expression; Gene Expression Regulation; Heart failure; Heart Failure, Systolic - diagnosis; Heart Failure, Systolic - metabolism; Heart Failure, Systolic - physiopathology; Hospitals, Veterans; Humans; Male; Middle Aged; Muscle Strength - physiology; Muscle, Skeletal - metabolism; skeletal muscle; Stroke Volume - physiology; Ventricular Function, Left - physiology; Heart failure; skeletal muscle; gene expression
• ISSN: 1071-9164; 1532-8414
• DOI: 10.1016/j.cardfail.2014.03.007

Abstract Background Declining physical function is common among systolic heart failure (HF) patients and heralds poor clinical outcomes. We hypothesized that coordinated shifts in expression of ubiquitin-mediated atrophy-promoting genes are associated with muscle atrophy and contribute to decreased physical function. Methods Systolic HF patients (left ventricular ejection fraction [LVEF] ≤40%) underwent skeletal muscle biopsies (nondominant vastus lateralis) and comprehensive physical assessments. Skeletal muscle gene expression was assessed with the use of real-time polymerase chain reaction. Aerobic function was assessed with the use of cardiopulmonary exercise and 6-minute walk tests. Strength capacity was assessed with the use of pneumatic leg press (maximum strength and power). Serologic inflammatory markers also were assessed. Results 54 male patients (66.6 ± 10.0 years) were studied: 24 systolic HF patients (mean LVEF 28.9 ± 7.8%) and 30 age-matched control subjects. Aerobic and strength parameters were diminished in HF versus control. FoxO1 and FoxO3 were increased in HF versus control (7.9 ± 6.2 vs 5.0 ± 3.5, 6.5 ± 4.3 vs 4.3 ± 2.8 relative units, respectively; P  ≤ .05 in both). However, atrogin-1 and MuRF-1 were similar in both groups. PGC-1α was also increased in HF (7.9 ± 5.4 vs. 5.3 ± 3.6 relative units; P  < .05). Muscle levels of insulin-like growth factor (IGF) 1 as well as serum levels of tumor necrosis factor α, C-reactive protein, interleukin (IL) 1β, and IL-6 were similar in HF and control. Conclusion Expression of the atrophy-promoting genes FoxO1 and FoxO3 were increased in skeletal muscle in systolic HF compared with control, but other atrophy gene expression patterns (atrogin-1 and MuRF-1), as well as growth promoting patterns (IGF-1), were similar. PGC-1α, a gene critical in enhancing mitochondrial function and moderating FoxO activity, may play an important counterregulatory role to offset ubiquitin pathway–mediated functional decrements.