Research Goals
The global aim of the CRG is to provide a platform for the members to work together to achieve their individual and mutual goals in molecular genetics, cell differentiation, animal models, and novel patient-oriented studies of phenomena leading to muscle atrophy or hypertrophy and in finding relevant therapies to prevent, cure or attenuate such diseases.
We propose 8 projects that can roughly be divided into studies of muscle differentiation and structure (Projects 1, 4, 6, 7, 8) and muscle metabolism (Projects 2, 3, 9). Projects 1, 4, 6, 7, 8, and 9 primarily address underlying pathophysiological mechanisms of disease. Projects 3, 6, and 7 include possible therapeutic applications. Projects 1, 2, and 3 are directed at cachexia, atrophy, and their prevention. Projects 2, 3, and 9 are dedicated to bedside, patient-oriented clinical research.
Faulty regulation of muscle growth is the source of clinically relevant muscular atrophy. This state of affairs occurs with immobilization and inactivity (Project 1, Gotthard/Huebner), with cachexia during chronic consumptive illnesses (Project 2, Doehner/Anker), and with critical illness myopathy (Project 3, Weber-Carstens/Spranger). A possible source of ideas to develop strategies against atrophy is the observation of animals during hibernation.
Perturbed muscle growth regulation can also lead to pathological muscle hypertrophy. In Project 4 (Vinkemeier), the nucleocytoplasmatic transport of transcription factors such as the SMADs will be investigated, as well as interactions with sarcomeric proteins under the conditions of hypertrophy and atrophy.
Patients with Dunnigan’s familial partial lipodystrophy have hypertrophied but faulty skeletal muscle, lose their subcutaneous fat, and develop the metabolic syndrome and type-2 diabetes. Project 9 (Jordan/Boschmann) is directed at elucidating altered metabolism in this disease.
Projects 6 and 7 shall investigate the detailed role of myostatin, a protein of the TGF-beta subfamily which is an important regulator of muscle mass. In project 6 (Spuler) a dysferlin-deficient mouse model will be investigated in terms of myostatin regulation. These mice develop a form of muscular dystrophy. Corresponding studies will be performed on human myocytes. Myostatin may also be of relevance in malignant skeletal muscle tumors. In Project 7 (Schuelke) myostatin will be investigated in rhabdomyosarcoma, a childhood sarcoma that currently cannot be effectively treated. Myostatin directs its signals via SMAD transcription factors as would be expected from a TGF-beta family member.
Ahnak, a tumor-associated protein in the sarcolemma, is involved in the development of so-called “enlargeosomes” that are responsible for the enlargement of muscle membrane structures, as well as their repair. There is recent evidence that ahnak binds dysferlin. In an ahnak knockout mouse the consequences of ahnak deficiency will be elucidated with regards to dysferlin expression. Furthermore, the consequences for ahnak expression and localization will be investigated in dysferlin deficient myoblasts (Project 8, Morano/Haase). The relationship between ahnak and dysferlin connects project 8 with project 6.
