Reduction In Skeletal Muscle Chloride Conductance Improves Contractile Force In Wildtype, But Not In Hyperkalemic Periodic Paralysis Mice

Abstract

Hyperkalemic periodic paralysis (HEPP) is an inherited, autosomal disorder characterized by myotonia and periodic paralysis in skeletal muscle. The hallmark of the disease is a severe sensitivity to the K+-induced force depression, the cause of the paralysis. Previous studies have provided evidence that the sensitivity to the K+-induced force depression can be alleviated when the Cl- conductance (GCl) is lowered. However, those studies were carried out at non-physiological temperatures (25°-30°C) and few stimulation frequencies. The overarching goal of this study was to examine whether manipulating GCl pharmacologically was a viable target for treating HEPP. This work sought to document the interactive effect of K+ and Cl- on force development in mouse skeletal muscle at 37°C, over a wide range of stimulation frequencies. Secondly, experiments were undertaken to determine if a reduction in GCl could protect against the severe K+ sensitivity in HEPP. The results show that in wildtype muscle, a reduction in GCl improved force generation at high [K+]e at stimulation frequencies that naturally occur in vivo for mouse EDL and soleus. While the effect in wildtype muscles was proof of principle that a reduction in GCl may be a potential approach to treat HEPP patients, the effects of reduced GCl at high [K+]e was quite variable in HEPP muscles. In a few cases, lowering GCl did improve force generation at high [K+]e. However, in most cases the decrease in GCl exacerbated the force depression at high [K+]e, suggesting that more studies will be necessary to understand the variability in the Cl- effect to conclude whether a decrease in GCl is a viable approach to treat HEPP patients.