Skeletal muscle myofibrillar protein metabolism in heart failure: relationship to immune activation and functional capacity

Abstract

LeWinter. Skeletal muscle myofibrillar protein metabolism in heart failure: relationship to immune activation and functional capacity. Am J Physiol Endocrinol Metab 288: E685-E692, 2005. First published November 23, 2004; doi:10.1152/ajpendo.00444.2004.-Chronic heart failure is characterized by changes in skeletal muscle that contribute to physical disability. Most studies to date have investigated defects in skeletal muscle oxidative capacity. In contrast, less is known about how heart failure affects myofibrillar protein metabolism. Thus we examined the effect of heart failure on skeletal muscle myofibrillar protein metabolism, with a specific emphasis on changes in myosin heavy chain (MHC) protein content, synthesis, and isoform distribution in 10 patients with heart failure (63 Ϯ 3 yr) and 11 controls (70 Ϯ 3 yr). In addition, we examined the relationship of MHC protein metabolism to inflammatory markers and physical function. Although MHC and actin protein content did not differ between groups, MHC protein content decreased with increasing disease severity in heart failure patients (r ϭ Ϫ0.748, P Ͻ 0.02), whereas actin protein content was not related to disease severity. No difference in MHC protein synthesis was found between groups, and MHC protein synthesis rates were not related to disease severity. There were, however, relationships between C-reactive protein and both MHC protein synthesis (r ϭ Ϫ0.442, P ϭ 0.05) and the ratio of MHC to mixed muscle protein synthesis (r ϭ Ϫ0.493, P Ͻ 0.03). Heart failure patients showed reduced relative amounts of MHC I (P Ͻ 0.05) and a trend toward increased MHC IIx (P ϭ 0.06). In regression analyses, decreased MHC protein content was related to decreased exercise capacity and muscle strength in heart failure patients. Our results demonstrate that heart failure affects both the quantity and isoform distribution of skeletal muscle MHC protein.The fact that MHC protein content was related to both exercise capacity and muscle strength further suggests that quantitative alterations in MHC protein may have functional significance. sarcopenia; cardiac cachexia; myosin heavy chain isoform; cytokine; actin RESEARCH OVER THE PAST TWO DECADES has identified an important role for skeletal muscle in reduced functional capacity in heart failure patients. Several abnormalities intrinsic to skeletal muscle, including muscle atrophy (7, 30) and diminished oxidative capacity (35), have been cited as factors contributing to physical disability. The mechanisms underlying these defects and their contribution to exercise intolerance and reduced muscle strength, however, remain unclear. The majority of studies that have examined the effect of heart failure on skeletal muscle have focused on oxidative capacity and/or mitochondrial function. In contrast, less is known about the impact of heart failure on myofibrillar proteins and their relationship to reduced functional capacity.Protein is the primary structural and functional macromolecule in skeletal muscle. From both quantitative and funct...

Skeletal muscle contractile protein function is preserved in human heart failure

“…Therefore, the questions remains as to what causes deficits in whole muscle function in heart failure patients. Recent studies from our laboratory have shown that heart failure promotes a reduction in skeletal muscle MHC protein content (31), presumably via downregulation of MHC transcription (27). As we clearly demonstrate in Fig.…”

“…Although many functional differences between fiber types have been ascribed to myosin composition (1,15), variation in the composition of thin-filament proteins, such as troponin C, I, and T isoforms (20,22,23), could also contribute. This point is particularly relevant to our results since our laboratory (31) and others (36) have shown alterations in fiber-type distribution in CHF, with a shift toward a more fast-twitch phenotype. To directly test whether variation in fiber type affects thinfilament function, we isolated native thin filaments from rat EDL and soleus muscles [composed primarily of fast-twitch and slow-twitch fibers, respectively (32)] and characterized their function using the in vitro motility assay.…”

“…Skeletal muscle biopsies were taken from the vastus lateralis muscle under local lidocaine anesthesia as previously described (31). Biopsies weighing between 100 and 150 mg were snap frozen in liquid nitrogen after adipose and connective tissues were removed and subsequently stored at Ϫ70°C.…”

“…Actin and MHC content were determined from tissue homogenates using gel electrophoresis, as described previously (31). Actin and MHC content were determined as a function of protein load.…”

“…Actin and MHC content were determined as a function of protein load. In addition, the relative MHC isoform content was determined on homogenates from a separate piece of tissue using gel electrophoresis, as described previously (31). MHC isoforms were expressed as a fraction of total MHC protein content determined by densitometry.…”