Matrix mechanics regulates muscle regeneration by modulating kinesin-1 activity

Area of Science:

• Biomedical Engineering
• Muscle Physiology
• Cell Biology

Background:

• Sarcopenia, characterized by reduced muscle mass and strength, is linked to impaired skeletal muscle regeneration.
• The impact of sarcopenic muscle's biomechanical properties on the myogenic program is not well understood.

Purpose of the Study:

• To investigate the role of matrix stiffness in controlling myogenic differentiation.
• To identify mechanisms by which biomechanical properties influence skeletal muscle regeneration in sarcopenia.

Main Methods:

• Development of a mouse model of sarcopenia to assess in vivo muscle stiffness.
• Establishment of an in vitro system to study matrix stiffness effects on myogenic differentiation.
• Analysis of kinesin-1 protein's role in mechanotransduction and its regulation by matrix stiffness.

Main Results:

• Sarcopenic muscle exhibits reduced stiffness in vivo.
• Matrix stiffness regulates kinesin-1 activity, affecting mitochondrial transport and glucose transporter GLUT4 translocation.
• Stiffer matrices enhance kinesin-1 activity, promoting myogenic differentiation and muscle regeneration, while softer matrices impair these processes.
• Enhancing kinesin-1 activity in sarcopenic mice improved satellite cell expansion, myogenic differentiation, and muscle regeneration.

Conclusions:

• Kinesin-1 acts as a crucial mechanotransduction hub, sensing matrix stiffness to regulate myogenic differentiation.
• Matrix stiffness directly impacts the efficiency of the myogenic program via kinesin-1.
• Targeting kinesin-1 activity presents a potential strategy for enhancing muscle regeneration in sarcopenia.