The effects of Suramin on Ca²⁺activated force and sarcoplasmic reticulum Ca²⁺release in skinned fast-twitch skeletal muscle fibers of the rat

Abstract

Suramin has long been used in the treatment of various human diseases. Intravenous infusions of Suramin are commonly administered to patients over extended periods of time but there are a number of significant contraindications with peripheral muscle weakness being one of the most frequently reported. Previous work has shown that even after a single infusion (300 mg kg−1) Suramin remains in skeletal muscle in effective concentrations (11.6 μg mL −1; 84 days) for prolonged periods. These observations provide a strong rationale for investigation of the specific effects of Suramin on skeletal muscle function. Single mechanically skinned fibers were directly exposed to Suramin (10, 100 or 500 μmol L−1) for defined durations (2–10 min) in controlled physiological solutions that mimic the intracellular ionic environment of a fiber. Suramin treatment (10–500 μmol L−1) directly affected the contractile apparatus in a dose‐dependent manner causing a decrease in Ca2+‐sensitivity (pCa50 = −log (Ca2+) concentration, where 50% of maximum Ca2+‐ activated force is produced) by 0.14 to 0.42 pCa units and reduction in maximum Ca2+‐activated force by 14 to 62%. Suramin treatment (100 μmol L−1 for 10 min and 500 μmol L−1 for 2 min) also caused development of a Ca2+‐independent force corresponding to 2.89 ± 4.33 and 16.77 ± 7.50% of pretreatment maximum Ca2+‐activated force, respectively. Suramin treatment (100 μmol L−1, 2 min) also increased the rate of sarcoplasmic reticulum (SR) Ca2+ release without significant changes in SR Ca2+ uptake. We report new functional effects for Suramin related to alterations in both the contractile apparatus and SR Ca2+‐handling of skeletal muscle that may contribute to the peripheral muscle weakness noted in human pharmacological treatments.

The effect of intrauterine growth restriction on Ca2+-activated force and contractile protein expression in the mesenteric artery of adult (6-month-old) male and female Wistar-Kyoto rats

“…A nonlinear regression, specifically single exponential association derived from equation 1 was used to fit the points of the curve for each preparation, using GraphPad Prism 6.01 (as described previously by Williams et al. ()).…”

“…The Ca 2+ -sensitivity of the contractile apparatus was ascertained by normalizing all submaximal force responses elicited to low pCa solution, to the maximum Ca 2+ -activated force, which was plotted against the pCa. A nonlinear regression, specifically single exponential association derived from equation 1 was used to fit the points of the curve for each preparation, using GraphPad Prism 6.01 (as described previously by Williams et al (2017)).…”