Mechanisms and therapeutic potential of modulating PGC‐1α to alter neuromuscular junction morphology and function
Prof. Christoph Handschin, Biozentrum, University of Basel
Abstract (Lay summary see below)
Healthy muscle function depends on a normal crosstalk between motor neurons and muscle fibers. The stability and function of neuromuscular junctions (NMJs) accordingly is impaired in many muscular dystrophies, including Duchenne muscular dystrophy. Furthermore, some neuromuscular diseases are directly caused by a degeneration of the NMJ, e.g. amyotrophic lateral sclerosis (ALS) or spinal muscular atrophy (SMA). We and others have shown that elevation of the peroxisome proliferator‐activated receptor γ coactivator 1α (PGC‐1α), a key regulator of endurance training adaptation in muscle, reduces fiber damage and atrophy and improves muscle functionality in a number of different muscle pathologies with very different etiologies. However, the molecular mechanisms that underlie this broad therapeutic effect are unknown. We have preliminary data indicating that in mice in vivo, muscle PGC‐1α alters the morphology, integrity and function of NMJs, surprisingly both on the post‐ as well as on the pre‐synaptic side, thus in the active zone of the motor neuron. Our project now aims at elucidating the retrograde signals that are controlled by PGC‐1α in muscle cells and subsequently modulate pre‐synaptic NMJ function. Second, we will investigate whether elevation of PGC‐1α in muscle, without or together with exercise interventions, has a beneficial effect in different mouse models for SMA, a disease that is caused by NMJ deterioration due to degeneration of motor neurons and muscle. In this disease, pharmacological elevation of PGC‐1α could potentially overcome the exercise intolerance of patients and subsequently allow an adjuvant therapy that can be combined with and improve exercise‐based interventions. Thus, we hope to elucidate a novel pathway of PGC‐1α‐controlled NMJ stabilization that could be targeted therapeutically in different muscular dystrophies.
Lay summary
Die Gesundheit des Skelettmuskels hängt von der reibungslosen Interaktion zwischen Muskel und Motorneuron ab. Dementsprechend ist in vielen Muskeldystrophien die Stabilität und Funktion der neuromuskulären Synapse beeinträchtigt. In unserem Projekt wollen wir jetzt studieren, wie der transkriptionelle Koaktivator PGC-1α (peroxisome proliferator-activated receptor γ coactivator 1α) die Morphologie und Funktion dieser Synapse beeinflusst. PGC-1α ist ein zentraler Regulator der Anpassung des Skelettmuskels an körperliche Aktivität. Zudem konnten wir und andere Forschungsgruppen zeigen, dass eine Erhöhung von PGC-1α im Muskel der entsprechenden Tiermodelle therapeutische Wirksamkeit gegen Muskelfaserschäden und –atrophie sowie für eine verbesserte Muskelfunktionalität entfaltet. Ein Teil dieses Effekts könnte durch eine Stabilisierung der neuromuskulären Synapse erklärt werden. Wir untersuchen am Tiermodell die molekularen Vorgänge, durch die PGC-1α die neuromuskuläre Synapse in der Muskelzelle und im Motorneuron an erhöhte Aktivität anpasst. Zudem wollen wir herausfinden, ob die durch PGC-1α regulierte Plastizität der Synapse auch in Muskelkrankheiten welche durch Defekte im Motorneuron hervorgerufen werden, therapeutisch wirksam sein könnten. Als Modell dazu studieren wir Spinale Muskelatrophie (SMA). Wir hoffen durch unsere Studien neue Erkenntnisse zu den molekularen Mechanismen der Krankheitspathologie, aber auch zusätzliche Therapiemöglichkeiten zu gewinnen.
Projekte
- Neue Forschungsprojekte ab 2024
- Die Bedeutung der Forschung
- Finanzierte Projekte
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