Sodium channels in fast and slow skeletal muscle

Skeletal muscle is an extremely heterogeneous tissue which has to fulfil various functional demands. The wide variety of mechanical performance is achieved by different muscle fibre types, each of which is specialised for certain challenges. Depending on its functional demands, each skeletal muscle of the body contains a unique composition of so called "fast" and "slow" muscle fibres, but this composition is not static, and the muscle fibres are capable of adapting their molecular composition by altered gene expression (i.e. fibre type conversion). Differences in the contractile properties of the fibre types have been causally linked to the expression of different isoforms of the myosin heavy chain (MHC) (e.g. Hilber & Galler, 1997a, b). Besides the MHC, other myofibrillar proteins, metabolic enzymes and calcium- (Ca2+) regulatory proteins do also exist as fibre type specific isoforms. However, very little is known about ion channels in the surface membrane of fast and slow skeletal muscle fibres. Sodium (Na+) channels play a central role in determining basal properties of muscle fibre types; they regulate their excitability. Fast fibres of mammals must be able to generate an action potential every few milliseconds, whereas fire frequencies in slow fibres do not exceed 20 Hertz. These different firing patterns place distinct functional demands on the Na+ channels of various muscle fibre types; i.e. Na+ channels of fast fibres should be able to gate more rapidly. These considerations raise an important question: Are Na+ channels, like many other proteins, specialised for their function in fast and slow skeletal muscle? In the present study, we will compare the functional properties of Na+ channels in cultured fast and slow skeletal muscle fibres. Na+ currents of these cells will be measured using patch clamp techniques. The aim of the present study is to characterise the functional properties of Na+ channels, and the factors that modulate these channels in fast and slow mammalian skeletal muscle. Experiments on intact muscle fibres provided clear evidence for fibre type specific properties of Na+ channels, but the origin of these differences between fast and slow muscle cells is unknown. The results of the present study will lead to a better understanding of how various types of skeletal muscle are able to fulfil their special functional demands. Moreover, we will study, if different isoforms of the Na+ channel do exist in fast and slow muscle fibres, or if the fibre type specific functional properties of Na+ channels are due to other modulatory factors such as the coexpression of ?1-subunits or intracellular modulators. Furthermore, we will study the effects of fast-to slow-fibre type conversion on Na+ channel function. This will show, if a switch in the contractile properties of muscle fibres, which occurs during fibre type conversion, is accompanied by a switch in Na+ channel expression. This would imply a link in the regulation of genes that encode the contractile proteins, and of genes encoding ion channels. Finally, we will test if the different functional properties of Na+ channels in fast and slow muscle are important for the pathophysiology of disease states (myotonia, malignant hyperthermia).

Each skeletal muscle of the body contains a unique composition of so-called "fast" and "slow" muscle cells (muscle fibres), each of which specialised for certain functional challenges. This composition is not static, and, e.g. triggered by physical training, the muscle fibres are capable of adapting their molecular composition by altered gene expression (i.e. fibre type transformation). Whereas several forms of cellular adaptations, which occur in the course of fibre type transformation, are well described, very little is known about possible adaptations of the electrophysiological properties of skeletal muscle cells. Such adaptations may involve changes in the expression and/or function of ion channels, and lead to altered excitability of muscle tissue. In our project, we studied electrophysiological adaptations of skeletal muscle cells in the course of fibre type transformation. Indeed, we could show that essential functional parameters of sodium currents changed in the course of "fast-to-slow" fibre type transformation. Thus, significant differences in the inactivation properties of sodium channels could be detected. These ion channels are of essential importance for the genesis and conduction of electrical impulses which control muscle contraction. The described differences are caused by an increased expression of the cardiac isoform (Nav 1.5), and a diminished expression of the skeletal muscle isoform (Nav 1.4) of the sodium channel. Thus, "fast-to-slow" fibre type transformation seems to lead to cardiac-like sodium channel function in skeletal muscle cells. These results implicate that the excitability of skeletal muscle tissue can be modified by external stimuli such as physical training. The results of this study have broadened the physiological knowledge about skeletal muscle and its remarkable adaptive capacity in response to functional demands. They may also contribute to a better understanding of skeletal muscle disorders which are caused by impaired cell excitability such as myotonia, periodic paralysis, and malignant hyperthermia. Of more general relevance, by identifying the factors regulating changes in ion channel expression and/or function, drug targets may emerge for the development of new therapeutic strategies in the treatment of disorders caused by hypo-, or hyper-excitability of various cell types, the so-called "transcriptional channelopathies". These involve common disease states such as chronic pain, seizures, hypertension and ischemic heart disease.