Annexin A2 Causes Motor Incoordination via Muscle-Cerebellum Axis in Sarcopenia

Area of Science:

• Gerontology
• Neuroscience
• Molecular Biology

Background:

• Sarcopenia, an age-related muscle disorder, leads to impaired balance and increased fracture risk.
• The cerebellum's role in motor control highlights the need to understand the muscle-cerebellum axis in sarcopenia.
• Investigating molecular mechanisms of sarcopenia-related imbalance is crucial for therapeutic development.

Purpose of the Study:

• To identify key secretory proteins involved in the muscle-cerebellum communication in aging.
• To elucidate the functional role of Annexin A2 (ANXA2) in sarcopenia-related muscle atrophy and motor deficits.
• To evaluate the therapeutic potential of isoliquiritigenin in mitigating sarcopenia symptoms.

Main Methods:

• 4D label-free proteomics to identify muscle-secreted proteins.
• Adeno-associated virus (AAV) mediated overexpression of ANXA2 in mice.
• RNA-sequencing and stereotactic injections to study ANXA2 mechanisms in muscle and cerebellum.
• Assessment of motor coordination and muscle function in aged mice treated with isoliquiritigenin.

Main Results:

• Aged mice exhibited impaired motor coordination and reduced muscle strength.
• Proteomics identified ANXA2 as a key secretory protein in aged skeletal muscle.
• ANXA2 exacerbated muscle atrophy by upregulating MuRF-1/Atrogin-1 and downregulating Neu2.
• ANXA2 targeted cerebellar CB2R, leading to motor incoordination.
• Isoliquiritigenin inhibited ANXA2, alleviating muscle atrophy and motor deficits without affecting anxiety.

Conclusions:

• ANXA2 is a critical mediator of the muscle-cerebellum axis in sarcopenia.
• ANXA2 contributes to muscle atrophy via Neu2 and motor incoordination via CB2R.
• Isoliquiritigenin shows therapeutic potential for sarcopenia by targeting ANXA2.