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

详细信息    查看全文

• 作者：Daniel E. Forman ; MD¹ ; ² ; ³ ; ^{deforman@partners.org" class="auth_mail} ; Karla M. Daniels ; MS³ ; Lawrence P. Cahalin ; PhD ; PT⁴ ; Alexandra Zavin ; BS¹ ; Kelly Allsup ; BS¹ ; Peirang Cao ; PhD⁵ ; Mahalakshmi Santhanam ; PhD⁵ ; Jacob Joseph ; MD² ; ³ ; Ross Arena ; PhD ; PT⁶ ; Antonio Lazzari ; MD⁷ ; ⁸ ; P. Christian Schulze ; MD ; PhD⁹ ; Stewart H. Lecker ; MD ; PhD⁸
• 关键词：Heart failure ; skeletal muscle ; gene expression
• 刊名：Journal of Cardiac Failure
• 出版年：June 2014
• 年：2014
• 卷：20
• 期：6
• 页码：422-430
• 全文大小：517 K

文摘

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