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PIEZO and TRP channels are receptors for physical stimuli such as mechanical touch and temperature in sensory neurons. As these receptors are localized in the plasma membrane, the modulation of their activities by membrane lipids has recently attracted attention. In this study, we focused on ether phospholipids (ePLs) enriched in neurons and analyzed their role in somatosensation using Drosophila. Reduced mechanosensory behavior was observed with ePL-synthesizing gene knockout or knockdown in PIEZO-expressing neurons. PIEZO activation was significantly augmented in the presence of ePLs. Furthermore, we observed that ePLs modulate the thermosensory behavior and reduce the temperature threshold of TRPA1. Finally, we revealed that ePLs affect membrane tension and lipid order of the plasma membrane in cultured cells. Our study identified ePLs as a modulator of a specific set of receptors for multiple somatosensory modalities, which underscores the significance of functional interaction between membrane lipids and sensory channel proteins.
Congenital cytomegalovirus (CMV) infection is the most common perinatal infection, affecting up to 0.5% of infants. This elicits long-term disabilities that include neuropsychiatric manifestations, such as intellectual disability, microcephaly. Despite its high prevalence, the underlying mechanism of how congenitally acquired CMV infection causes brain pathology remain unknown. Here, we discovered the molecular interplay of key host (DISC1 and promyelocytic leukemia [PML]) and viral (immediate early 1 [IE1]) proteins within the neural progenitor cells, which underlay an attenuated neural progenitor proliferation in congenital CMV infection. Abolishing the viral IE1 protein by delivering IE1-targeting CRISPR/Cas9 to fetal brain rescued this progenitor cell deficit, a key pathology in congenital CMV infection. A selective targeting to a viral-specific protein by the CRISPR/Cas9 system is minimal in off-target effects. We further observed that CMV-encoded IE1 protein interferes with host PML-DISC1 interaction, resulting in disturbance of the Notch pathway in vitro and in embryonic brains. Therefore, we believe that a pivotal role of IE1 in an attenuated neural progenitor proliferation in the developing cortex through its interfering with interaction between host DISC1 and PML proteins.
Myostatin inhibition is well-known as a promising strategy to induce skeletal muscle hypertrophy. Midsized peptides are currently noted as a new modality in broad drug development. Our previous studies identified a series of myostatin inhibitory peptides, including the 16-mer D-peptide inhibitor MID-35. However, the detailed pharmacological analysis of muscle growth provided by intramuscularly injected MID-35 has not been investigated. Additionally, since sphingosine 1-phosphate (S1P), one of the bioactive sphingolipids, is involved in the regulation of muscle mass, it is vital to explore whether MID-35 treatment affects the S1P metabolism. Here, we analyzed alterations induced by MID-35 administration in the tibialis anterior muscles of young, adult, and aged mice. Muscle differentiation-related markers (Pax7/Myod1/Myog) and atrophy-related markers (Trim63/Fbxo32) were robustly increased and decreased, respectively, within 3 days, and muscle weight gain first appeared 14 days later; intriguingly, the hypertrophy was sustained for 12 weeks. An increase in centralized nuclei and Pax7-positive signals in MID-35-treated muscles corroborated muscle regeneration associated with muscle satellite cells (mSCs). Additionally, changes in the bioactive sphingolipid metabolism were observed. In young and adult mice, the amount of S1P was significantly increased on day 3, suggesting that S1P may assist in the activation of the mSCs. Meanwhile, aging affects S1P metabolism, resulting in no significant increase in the S1P level in aged mice. This basic study using MID-35 newly proposes the interaction between myostatin signaling and bioactive sphingolipid metabolism in the muscle hypertrophic reaction and would accelerate further mechanistic evaluation, including the maintenance of the hypertrophic state.
