Differential Contractile Impairment of Fast- and Slow-Twitch Skeletal Muscles in a Rat Model of Doxorubicin-Induced Congestive Heart Failure

Abstract

Congestive heart failure (CHF) is associated with exercise intolerance that cannot be entirely explained by hypoperfusion of the skeletal muscles. We studied the contractile properties of fast-twitch (extensor digitorum longus; EDL) and slow-twitch (soleus; SOL) skeletal muscles in doxorubicin-induced CHF in rats, and evaluated the defective steps of excitation-contraction coupling. Both types of muscles-obtained from CHF rats displayed significant reduction in twitch and tetanic contractions. Twitch half-relaxation times of CHF SOL muscles were prolonged while there was no significant difference in EDL muscles. High K⁺ application induced lower contracture amplitudes in CHF muscles. Caffeine-induced contractures were significantly diminished in CHF SOL. Verapamil application depressed tetanic contractions in all preparations while depression was more pronounced in CHF SOL. Immunohistochemistry revealed reduced expression of sarcoplasmic reticulum Ca²⁺-ATPase-1 and -2 in CHF EDL and in CHF SOL, respectively. Sarcolemmal excitability and spontaneous neurotransmitter release were unaffected since resting membrane potential, action potential and miniature end-plate potentials were unaltered in CHF muscles. We conclude that CHF induces contractile impairment that occurs predominantly in rat slow-twitch skeletal muscles. Our results suggest that this muscle-type-specific effect of CHF is related to the defective intracellular Ca²⁺ release and uptake mechanisms and reduced sarcolemmal-dihydropyridine-sensitive Ca²⁺ channel activity.

Differential morphofunctional characteristics and gene expression in fast and slow muscle of rats with monocrotaline-induced heart failure

“…However, contraction fall time in HF SOL muscle was higher than in the control group. This finding is in accordance with to Ertunc et al (2009) who showed that HF leads to prolongation of twitch fall time only in SOL muscle. Kuno et al (1988) reported that muscles with higher proportions of type II fibers (fast twitch and glycolytic metabolism) have longer fall times than muscles with a predominance of type I fibers (slow twitch and oxidative metabolism).…”

The anticancer agent doxorubicin disrupts mitochondrial energy metabolism and redox balance in skeletal muscle

“…Our previous work [6-8], along with others [29, 54, 55], demonstrates skeletal muscle from healthy rodents exposed to doxorubicin show a decrease in muscle strength and an accelerated rate of fatigue. Muscle weakness can result from impaired membrane excitability, calcium release/uptake, and/or myofibrillar protein function.…”

Effects of chronic heart failure on neuronal nitric oxide synthase‐mediated control of microvascular O2 pressure in contracting rat skeletal muscle

“…Therefore, the data indicate that the nNOS‐mediated effects on contractile function and economy are curtailed in CHF rats. By extension, the muscle contractile dysfunction evident in CHF subjects (Perreault et al 1993; Lunde et al 2002; Ertunc et al 2009) must occur via dysregulation/dysfunction of other mechanisms occurring simultaneous with nNOS downregulation. For example, CHF induces elevated intracellular iNOS, which correlates with exercise intolerance (Hambrecht et al 1999), and impaired sarcoplasmic reticulum function and calcium regulation (Perreault et al 1993; Reiken et al 2003), which likely contribute to contractile dysfunction in CHF.…”