Ion channel plasticity in transforming skeletal muscle

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 the muscle fibres are capable of adapting their molecular composition by altered gene expression (i.e. fibre type transformation). Whereas changes in the expression of contractile proteins and metabolic enzymes in the course of fibre type transformation are well described, very little is known about possible adaptations in 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. We recently showed that, in differentiated skeletal muscle cells, basic functional parameters of currents through voltage-gated sodium channels were significantly altered in the course of fast-to-slow fibre type transformation. Importantly, this suggested that differentiated skeletal muscle can adapt its electrophysiological properties, and thus, its excitability. However, the dimension of ion channel plasticity and its regulation in skeletal muscle remains unclear. In this project, experimentally induced fibre type transformation will be used as an in vitro model to investigate electrophysiological adaptations in differentiated skeletal muscle. A main aim is to identify changes in the expression and function of various ion channel types which play crucial roles in cell excitability. Our approach will also allow investigation of the mechanisms underlying, and the signalling pathways regulating these structural and functional changes. In addition, proteomic analyses will be used to identify possible new regulators of ion channel plasticity. The results of this study are expected to broaden the physiological knowledge about skeletal muscle and its adaptive capacity in response to external stimuli such as enhanced activity or disuse. They may lead 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.

Ion channels in the cellular membrane of skeletal muscle cells provide the basis for the electrical excitability of skeletal muscles. They are a prerequisite for the transferability of electrical signals from nerve to muscle, and for the initiation of muscle contraction. 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 the muscle fibres are capable of adapting their molecular composition by altered gene expression (i.e. fibre type conversion). Whereas changes in the expression of contractile proteins and metabolic enzymes in the course of fibre type conversion are well described, very little is known about possible adaptations in 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. This project aimed at the investigation and characterisation of changes in ion channel expression and function in transforming skeletal muscle. We uncovered a significant degree of ion channel plasticity in skeletal muscle, indicating that muscle can adapt its electrophysiological properties, and thus, its excitability. Besides in the course of skeletal muscle fibre type conversion, ion channel expression and function in muscle cells can also be selectively modulated by treatment with synthetic small molecule compounds. Thereby, skeletal muscle cells with more cardiac-like electrophysiological properties can be generated. Finally, we found significant ion channel impairments in diseased muscle, whereby Duchenne muscular dystrophy was used as disease model. Here, the electrophysiological abnormalities were especially pronounced in the dystrophic heart. The results of these studies not only broadened the physiological knowledge about skeletal muscle and its adaptive capacity in response to external stimuli such as enhanced activity, disuse and treatment with chemical agents. 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. Moreover, the synthetic small molecule- induced generation of skeletal myoblasts with more cardiac- like electrophysiological properties represents a promising step towards a safer and more efficient cell therapy for the diseased heart. Considering that cardiovascular diseases are a major health problem worldwide, this also implies economic benefits. Finally, our discovery of the existence of severe ion channel impairments in the dystrophic heart even before cardiomyopathy development suggests a new therapeutic concept for muscular dystrophy patients: early treatment with drugs that modulate cardiac voltage-gated ion channels in order to prevent dystrophic cardiomyopathy.