Widespread neuronal hemokinin-1 expression in motor regions and its protective role in age-related impairment

Hemokinin-1 (HK-1) regulates several processes in the central and peripheral nervous systems, including musculoskeletal functions; however, its involvement in age-related motor coordination and muscle strength remains unknown. Therefore, these were investigated here with HK-1-deficient mice together with the expression patterns in the mouse and human motor coordination centers. Tac4 gene expression, encoding HK-1, was detected by RNAscope, and its age-dependent changes in the cerebellum and soleus muscle were analyzed by qPCR. The rotarod and static rod tests were used to measure motor coordination, while the horizontal bar and grid tests assessed muscle strength in 3-4 (young), 12 (middle-aged), and 18-month-old (old) C57BL/6 wildtype (WT) and HK-1-deficient male and female mice. HK-1 mRNA was abundant in motor cortices, basal ganglia, and cerebellum, showing a significant increase with age. Motor coordination gradually declined with aging in WT mice of both sexes. This age-dependent reduction in motor coordination was significantly enhanced by HK-1 deficiency in middle-aged males but not females. Additionally, muscle strength was also remarkably worse in old WT mice, with a significantly greater decline in males. HK-1 deletion resulted in improved muscle strength in middle-aged male mice, but interestingly worsened function in the old groups of both sexes. HK-1 exerts age- and sex-dependent effects on motor coordination with a predominantly protective action on aging-induced decline in males. This might be explained by its high expression in all motor regions of the brain. Meanwhile, its function in regulating muscle strength is more complex, with a protective role only evident in old age.