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. 2024 Jul 23;25(15):8018. doi: 10.3390/ijms25158018

Figure 9.

Figure 9

Overview of the main molecular elements of the neurotransmission signalling altered in ageing EDL muscles. Image information: Protein levels of those molecules represented in (1) green are increased, (2) in red are decreased, and (3) in blue are maintained in ageing muscles compared with young muscles. Related to the neurotrophic pathway, #1, there is a change in the stoichiometry of the BDNF and NT-4 neurotrophins, because of the increased levels of NT-4. #2, TrkB.T1 protein levels are decreased, increasing the TrkB.FL/T1 ratio, and p75NTR is also decreased. #3, TrkB.FL direct downstream transducer PLCγ (and its phosphorylated form) do not change in ageing EDL muscles. #4, The protein level and the cytosol/membrane distribution of the presynaptic phosphorylated downstream PDK and PKCβI and PKCε isoforms is maintained in ageing muscles. #5, The protein levels of M1-subtype muscarinic receptor are maintained, and #6 the protein level of the M2-subtype muscarinic receptor is reduced. #7, The levels of the M1 mAChR downstream transducer PLCβ and M2 mAChR downstream transducer adenylyl cyclase are maintained. The only change observed relative to its downstream PKA kinase, #8, is the increased level of the PKA subunit RIα. As stated, the upregulation of this regulatory subunit may be linked to the reduction in pCREB in the postsynaptic site, #9. #10, cRaf and MAPK, kinases regulated by neurotrophic and muscarinic pathways, are unaffected by ageing. Both PKC and PKA regulate the SNARE-SM ACh release complex. #11. There is an imbalance in the SNARE-SM complex proteins Munc18-1 and SNAP-25 (and their phosphorylated forms). Although pMunc18-1 phosphorylated in S241 does not change, there is a decrease in pMunc18-1 (S313) and an increase in Munc18-1 protein levels in ageing muscles. #12, The SNAP-25 protein level does not change, or the PKA-dependent pSNAP-25 (T138). However, the cPKCβI- and nPKCε-dependent pSNAP-25 (S187) is greatly reduced in ageing. Despite these modifications, there is no difference in the membrane and cytosol distributions of these proteins between young and ageing muscles. Finally, #13, although there is a strong diminution of the P/Q type voltage-gated calcium-channel (VGCC) in ageing, #14, all proteins related to ACh and recycling synaptic vesicles (acetylcholinesterase, choline transporter in the plasmalemma, cholin acetyl transferase, and vesicular acetylcholine transporter) are unmodified in ageing muscles.