Skeletal muscle protein metabolism in human heart failure

Abstract

Purpose of review This review considers evidence that the clinical condition of heart failure (HF) alters skeletal muscle protein synthesis and/or breakdown to promote skeletal muscle wasting and functional decrements that ultimately contribute to the symptomology of the disease. Recent findings Advanced heart failure is frequently accompanied by muscle atrophy and a cachectic phenotype. Protein metabolic derangements that promote this phenotype are understudied and poorly understood. Instead, most investigations have evaluated regulatory hormones/signaling pathways thought to be reflective of protein synthesis and breakdown. Several of these recent studies have provided exciting data suggesting that the dysfunctional myocardium releases catabolic agents that could promote the skeletal muscle myopathic phenotype either directly or through modulation of other regulatory systems (eg, energy balance). Summary While our understanding of skeletal muscle atrophy and dysfunction in heart failure is limited, recent studies have provided clues about the nature and timing of protein metabolic dysfunction. More specifically, skeletal muscle protein metabolic derangements likely evolve during periods of disease-related stress (ie, acute disease exacerbation and hospitalization) and potentially derive in part, from signals promoted in the damaged/dysfunctional myocardium. Despite these compelling studies, there is a surprising lack of data regarding the nature or timing of specific protein metabolic defects in HF.

Cardiac cachexia and muscle wasting: definition, physiopathology, and clinical consequences

“…17 As can be seen from the previous section, skeletal muscle wasting can be both a cause or a consequence of cachexia. 26 Increased catabolism and body weight loss are also associated with a decrease in respiratory muscle strength. 73 It was recently observed that fat mass wasting is also predictive of adverse outcome.…”

“…As anabolic pathways are probably insufficient to recover muscle size and function to prehospitalization levels, efforts to prevent disease exacerbation should be emphasized. 26 Finally, it has been showed that increased catabolism not only occurs in skeletal muscle but also in adipose tissue.…”

“…40 Also in heart failure, muscle loss pattern depends on experimental model, and both a slow-to-fast and a fast-to-slow fiber-type shift has been described. 33,41 Recently, Callahan and Toth 26 suggested that increased proteolysis and reduced protein synthesis mainly occur during disease exacerbation and hospitalization due to increased inflammatory and neurohormonal activation. As anabolic pathways are probably insufficient to recover muscle size and function to prehospitalization levels, efforts to prevent disease exacerbation should be emphasized.…”

“…22,33 Muscle disuse by bed rest can also contribute to protein catabolism. 26 The most important consequence of increased protein degradation is a reduction in myocyte cross-sectional area and muscle mass, which contributes to a reduction in physical performance and daily living activities. 21,[34][35][36][37][38] As well as by increased proteolysis, reduced muscle mass can also be caused by apoptosis or necrosis.…”

“…24,25 Enhanced proteolysis is the most consistent finding, whereas there is limited evidence for reduced protein synthesis. 26 The following major proteolytic pathways can be found in skeletal muscle: lysosomal, Ca 2+ dependent, caspase dependent, and ubiquitin-proteasome dependent. 27 One of the most important pathways responsible for intracellular degradation of striated muscle proteins is the ubiquitin-proteasome system.…”