Modelling the coupling of the M-clock and C-clock in lymphatic muscle cells

Area of Science:

• Physiology
• Computational Biology
• Biophysics

Background:

• Lymphoedema, a chronic fluid accumulation, stems from lymphatic vascular dysfunction, often secondary to cancer treatments.
• Lymphatic collecting vessel contractions, driven by electrochemical oscillations, are crucial for fluid return.
• Current understanding of lymphatic muscle cell excitation mechanisms is limited, hindering pharmacological treatment development.

Purpose of the Study:

• To develop a computational model of lymphatic muscle cell bioelectric activity.
• To investigate the interplay between membrane voltage (M-clock) and intracellular calcium (C-clock) oscillations.
• To provide a framework for identifying therapeutic targets for lymphoedema.

Main Methods:

• Modification of an existing computational model (Imtiaz et al.) for lymphatic muscle cells.
• Inclusion of voltage-dependent gating for L-type calcium channels to enable independent M-clock oscillations.
• Application of phase-plane analysis to study M-clock and C-clock dynamics and their interactions.

Main Results:

• The proposed model successfully simulates M-clock oscillations, similar to the FitzHugh-Nagumo model.
• The model demonstrates how M-clock oscillations can drive C-clock oscillations, fitting recent experimental data.
• Phase-plane analysis provides insights into the coupled dynamics of the M-clock and C-clock.

Conclusions:

• The developed computational model offers a novel approach to understanding lymphatic muscle electrophysiology.
• This model can elucidate the mechanisms underlying lymphatic dysfunction and lymphoedema.
• The findings have the potential to guide the development of targeted pharmacological therapies for lymphoedema.