Slowing Loss of Motor Function by Inhibiting VPS-34 in the Neuromuscular Junction

Today's open access paper discusses a way to slow neuromuscular junction aging, and thereby age-related loss of muscle function. Loss of muscle strength, dynapenia, and loss of muscle mass, sarcopenia, are characteristic of aging. These declines contribute to age-related frailty directly and evidently, but it is also worth noting that muscle tissue is metabolically active, and appears to contribute beneficial signal molecules to the circulation, collectively called myokines. Loss of muscle tissue likely has a harmful effect on overall metabolism via this mechanism.

What is the chain of cause and consequence that leads to the loss of muscle mass and strength? As is always the case, connections to fundamental mechanisms of aging are up for debate, but when it comes to more proximate contributing causes, the two most interesting lines of inquiry, to my eyes, are (a) loss of muscle stem cell activity, directly causing a decline in tissue maintenance via a smaller supply of new somatic cells, and (b) dysfunction in the neuromuscular junction that connects the nervous system to muscle tissue. Muscle tissue depends on innervation for growth and regeneration cues, and thus this can also cause a decline in tissue maintenance.

Partial inhibition of class III PI3K VPS-34 ameliorates motor aging and prolongs health span

In this study, we designed a fast and efficient genome-wide screening assay in C. elegans to systematically identify potential regulators of motor aging. Among the top hits, we functionally validated the role of VPS-34 in regulating motor aging and revealed its cell type-specific mechanisms. VPS-34 is the class III phosphatidylinositol 3-kinase that phosphorylates phosphatidylinositol (PI) to phosphatidylinositol 3-phosphate (PI(3)P), regulating motor function in aged but not young worms.

Contrary to popular belief that life span and health span are strongly correlated, the global increase of life expectancy over the past decades is rarely accompanied by increased health span. Since aging is characterized by functional decline of multiple organs and tissues, the key to healthy aging is to delay or rescue the decline of essential physiological functions. Motor independence is strongly associated with the quality of life of elderly people, yet motor aging is a common, conserved biological process from worms to humans, leading to frailty, loss of motor independence, falling, and even death. To date, it is still challenging to identify evolutionarily conserved mechanisms that can be exploited to delay or ameliorate motor aging.

Combining genetics, pharmacology, and in situ electrophysiology, we demonstrated that partial inhibition of VPS-34 significantly improved neuromuscular synaptic transmission and the muscle integrity, which ameliorate motor aging in both worms and mice. Previous studies have identified motor aging-associated regulators through candidate approaches, which act in either motor neurons/neuromuscular junctions or skeletal muscles. To our knowledge, VPS34 is the first reported gene that simultaneously regulates neurotransmission of motor neurons and muscle integrity during aging, likely through cell type-specific mechanisms. Thus, it is a promising target that can be exploited to improve both aged neurons and muscle.

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