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

作者：Forman Daniel E^*; Daniels Karla M; Cahalin Lawrence P; Zavin Alexandra; Allsup Kelly; Cao Peirang; Santhanam Mahalakshmi; Joseph Jacob; Arena Ross; Lazzari Antonio; Schulze P Christian; Lecker Stewart H

来源：Journal of Cardiac Failure, 2014, 20(6): 422-430.

DOI：10.1016/j.cardfail.2014.03.007

• Heart failure
• skeletal muscle
• gene expression

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-1 alpha 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 alpha, C-reactive protein, interleukin (IL) 1 beta, 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-1 alpha, a gene critical in enhancing mitochondrial function and moderating FoxO activity, may play an important counterregulatory role to offset ubiquitin pathway-mediated functional decrements.

• 出版日期2014-6