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

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, inter-leukin (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 pathwayemediated functional decrements.

Resveratrol protects against doxorubicin‐induced cardiotoxicity in aged hearts through the SIRT1‐USP7 axis

“…However, the transcript level of Foxo1, but not those of MAFbx and MuRF‐1, is elevated in the vastus lateralis muscle of patients with systolic heart failure (Forman et al . ). Intriguingly, the results of the present study showed that a concomitant increase of acetylated Foxo1 and MuRF‐1 induced by doxorubicin treatment was observed only in the hearts of young but not aged mice.…”

Skeletal muscle wasting in cachexia and sarcopenia: molecular pathophysiology and impact of exercise training

“…The UPS has been shown to act in a number of cachectic conditions, with an upregulation of proteins involved in the proteasome pathway such as polyubiquitins, Ub fusion proteins, the Ub ligases MAFbx, and MuRF‐1, detected in animal models of diabetes mellitus, uremia, and also cancer . However, whether the UPS plays a central role in HF seems less clear, as some but not all patient studies have found muscle biopsies to have an increased MuRF‐1 and MAFbx expression. That a coronary artery ligation model of HF in rats has also shown muscle wasting and higher proteasome activity in the plantaris and soleus, reinforces the importance of the UPS in cardiac cachexia.…”

Exercise and the Cardiovascular System

“…In patients with HFpEF, as well as in patients with systolic cardiac dysfunction, the degree of exercise intolerance is not directly related to the degree of cardiac weakness but somewhat surprisingly, the symptoms of dyspnea and fatigue in HF or often directly related to abnormalities of skeletal musculature in HF, 101 which has been reviewed in detail elsewhere. 102 …”