Contraction and Intracellular Ca ²⁺ Handling in Isolated Skeletal Muscle of Rats With Congestive Heart Failure

Abstract

Abstract-A decreased exercise tolerance is a common symptom in patients with congestive heart failure (CHF). This decrease has been suggested to be partly due to altered skeletal muscle function. Therefore, we have studied contractile function and cytoplasmic free Ca 2ϩ concentration ([Ca 2ϩ ] i , measured with the fluorescent dye indo 1) in isolated muscles from rats in which CHF was induced by ligation of the left coronary artery. The results show no major changes of the contractile function and [Ca 2ϩ ] i handling in unfatigued intact fast-twitch fibers isolated from flexor digitorum brevis muscles of CHF rats, but these fibers were markedly more susceptible to damage during microdissection. Furthermore, CHF fibers displayed a marked increase of baseline [Ca 2ϩ ] i during fatigue. Isolated slow-twitch soleus muscles of CHF rats displayed slower twitch contraction and tetanic relaxation than did muscles from sham-operated rats; the slowing of relaxation became more pronounced during fatigue in CHF muscles. Immunoblot analyses of sarcoplasmic reticulum proteins and sarcolemma Na ϩ ,K ϩ -ATPase showed no difference in flexor digitorum brevis muscles of sham-operated versus CHF rats. In conclusion, functional impairments can be observed in limb muscle isolated from rats with CHF. These impairments seem to mainly involve structures surrounding the muscle cells and sarcoplasmic reticulum Ca Key Words: heart failure Ⅲ skeletal muscle Ⅲ fatigue Ⅲ intracellular Ca 2ϩ handling D ecreased fatigue resistance and skeletal muscle weakness are important symptoms in humans with congestive heart failure (CHF). The reason for the decreased fatigue resistance is not clear. Often, there is no clear correlation between the degree of heart dysfunction and the decrease in exercise tolerance. 1 This suggests that there could be functional impairments within the skeletal muscles that are due to, for instance, alterations in the local environment with restricted local blood flow. 2 In addition, numerous studies have been focused on possible abnormalities in skeletal muscle cells, and significant changes have been found both at the mRNA and protein levels. Generally observed changes in skeletal muscle cells in CHF include a shift of myosin heavy chain distribution toward more fast-type myosin heavy chain, 3-5 altered expression of sarcoplasmic reticulum (SR) Ca 2ϩ -ATPase (SERCA), 6,7 and in later stages, decrements in mitochondrial enzymes and muscle cell atrophy. 8 Functional studies of limb muscle function in CHF are more sparse. One study on bundles of muscle fibers from the fast-twitch extensor digitorum longus (EDL) muscles of rats showed marked dysfunction in CHF with Ϸ50% reductions in tetanic Ca 2ϩ and force and markedly accelerated fatigue development, which was not due to muscle cell atrophy. 9 There seems to be a discrepancy between these very dramatic functional changes and the relatively subtle changes of muscle protein levels observed in muscles from CHF subjects. In accordance, a more recent study showed more mode...

Enhancing calstabin binding to ryanodine receptors improves cardiac and skeletal muscle function in heart failure

“…Studies from our laboratory have demonstrated defective function of RyR1 channels in HF skeletal muscle, which were analogous to those found in RyR2 channels in failing myocardium: PKA hyperphosphorylation of RyR1 and depletion of calstabin-1 (10,27). These findings suggest that defects in RyR1 function could alter intracellular Ca 2ϩ handling and contribute to early fatigue in HF skeletal muscle (40). The present study shows that fixing the defect in RyR1 results in improved performance of HF skeletal muscle, providing important support for the model in which defective regulation of RyR1 plays a role in HF symptoms, including shortness of breath and reduced exercise tolerance.…”

“…Indeed, observed changes in skeletal muscle cells in HF include a decrease in oxidative enzymes, a shift from slowtwitch to fast-twitch fibers (38), and impaired O 2 utilization (39). In several cases, alterations in SR Ca 2ϩ handling have been documented in skeletal muscle from experimental HF models (40,41). Skeletal muscle Ca 2ϩ transients in animals with HF typically exhibit reduced amplitude and a prolonged relaxation, consistent with altered expression levels of SERCA (41).…”

Skeletal muscle contractile protein function is preserved in human heart failure

“…This contractile deficit at the whole muscle level has been observed in isolated muscle tissue in animal models (16,21) and in chemically skinned, single muscle fibers in humans (26), suggesting that the heart failure syndrome promotes contractile dysfunction at the level of the myofilaments. In the present study, we investigated the role of individual myofilament components in the decreased skeletal muscle function of heart failure patients.…”

Relevância e tratamento das lesões características da insuficiência cardíaca na musculatura esquelética

“…32 Contrário a esses achados, 33 não encontraram diferenças na expressão de isoformas de SERCA, de receptor para rianodina (RR) e de diferentes subunidades do trocador Na + -Ca 2+ (NCX) utilizando os músculos sóleo e flexor curto dos dedos de ratos controle e ratos com insuficiência cardíaca induzida por ligadura da artéria coronária esquerda. Os resultados controversos do efeito da insuficiência cardíaca na expressão de proteínas envolvidas no transiente de Ca 2+ podem ser explicados por níveis de gravidade e etiologias de insuficiência cardíaca distintos, diferentes espécies estudadas, músculos utilizados distintos e/ou diferentes métodos de análise.…”