Background 
Cancer-induced cachexia is a complex multifactorial syndrome characterized by loss of muscle mass and function that affects up to 80% of cancer patients which contributes to the morbidity and mortality of the disease. Despite the extensive research on cancer cachexia, its exact etiology remains unknown. There is also no consensus on effective treatment for the loss of muscle mass, which subsequently impacts the tolerance and response to anti-cancer therapies. Furthermore, little is known about the effect of muscle wasting on the neuromuscular junction (NMJ), the vital synaptic connection between the motor neuron and skeletal muscle. The primary purpose of this study is to analyze the stability of the NMJs from cachectic muscles during the initiation and progression of the muscle-wasting event. To this end, we use the genetically engineered mouse model of colorectal cancer (Apc) Min/+ that has shown tumor growth and cachexia. 

Methods 
Sternomastoid, gastrocnemius, extensor digitorum longus, soleus, and diaphragm muscles were extracted from (Apc) Min/+ and age-matched controls at 16 and 24 weeks of age. The muscles were then fixed in 4% paraformaldehyde and bathed with Alexa488™ alpha-bungarotoxin to specifically label nicotinic acetylcholine receptors (nAChRs) at the postsynaptic junctional folds. Fluorescently labeled muscles were then imaged at the confocal microscope to analyze the synapse morphology, or with an inverted fluorescence microscope to quantify fluorescence intensity. The area and the density of nAChRs were then analyzed using ImageJ. To capture relevant changes in the NMJs, we performed in vivo experiments to determine the turnover rate of nAChRs at the synapse before severe weight loss occurred. To this end, we labeled sternomastoid muscles in vivo and assessed fluorescence intensity decay over time. 

Results 
At early stages of cancer-induced cachexia (16 weeks), all muscles except sternomastoid showed a significant decrease in nAChRs density in (APC) Min/+ mice compared to controls. In advanced stages of cachexia (24 weeks), all muscles from (APC) Min/+ mice showed a significant decrease in nAChRs density. All muscles showed a significant decline in the total NMJ area in (APC) Min/+ at 16 weeks and 24 weeks. 

Conclusion 
The decreased nAChR density and NMJ area in both fast and slow twitch muscles demonstrates postsynaptic NMJ alteration in cancer-induced cachectic mice. Analysis of presynaptic cells (motor neuron and Schwann cell) will be performed to further look at the pathology of the NMJ in cancer-induced cachexia, as well as younger mice to determine when the degeneration starts. 


The Impact of Cancer-induced Cachexia on the Neuromuscular Synapse

 Hematology / Oncology / Pathology

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