IF a hydrocarbon-stapled peptide (SP-RNC) designed to mimic the Raptor N-terminal caspase-like domain (RNC) β-sheet/α-helix contact surface and competitively occupy mTOR N-HEAT repeats 12–13 and M-HEAT repeats 20–23 (residues ~800–1300, spanning the ~500–1000 Ų convex ridge and bridge region) is administered via intramuscular depot injection (weekly, estimated 1–10 mg/kg local dose) to aged (24-month) male C57BL/6J mice with established sarcopenia,

THEN neuromuscular junction (NMJ) structural integrity — quantified by acetylcholine receptor (AChR) endplate fragmentation score, innervation ratio (co-localisation of NF-M/SV2 with BTX-labelled endplates), and motor endplate area by confocal immunofluorescence — will be restored ≥25% toward young-adult (4-month) reference levels within 12 weeks, with a secondary improvement of ≥15% in grip strength and rotarod endurance, while preserving lean body mass (unlike systemic rapamycin),

BECAUSE the following mechanistic chain is supported by synthesis of the evidence set:

1. Sustained mTORC1 hyperactivation is a muscle-intrinsic driver and structural hallmark of sarcopenia that converges pathologically on the NMJ; long-term systemic rapamycin partially preserves NMJ architecture but produces progressive systemic lean body mass loss, demonstrating that untargeted mTOR inhibition is an insufficient and costly repair strategy (NMJ-sarcopenia convergence)[https://doi.org/10.1038/s41467-020-18140-1]

2. The mTOR-Raptor interaction is mediated by a structurally defined ~500–1000 Ų flat PPI surface where Raptor's RNC β-sheet/α-helix elements engage mTOR N-HEAT repeats 12–13 and M-HEAT repeats 20–23; because Raptor is exclusive to mTORC1 (not mTORC2), disrupting this surface achieves complex-selective inhibition that rapamycin's FRB/FKBP12 allosteric mechanism does not fully recapitulate, particularly for rapamycin-insensitive mTORC1 outputs (structural context)[https://pmc.ncbi.nlm.nih.gov/articles/PMC5205667/][https://pmc.ncbi.nlm.nih.gov/articles/PMC6325617/]

3. mTORC1 hyperactivation at aged NMJs suppresses autophagy via ULK1 phosphorylation, causing accumulation of damaged mitochondria, ubiquitinated protein aggregates, and structurally dysfunctional synaptic components within perisynaptic Schwann cells and motor terminals; disrupting mTOR-Raptor at the NMJ would de-repress ULK1, reactivating autophagy-mediated clearance of this accumulated structural damage — a repair mechanism analogous to what mTOR-independent autophagy activators (e.g., CCT020312) achieve in tauopathy/prionopathy models (autophagy-repair link)[https://doi.org/10.1101/2022.09.29.509997]

4. [SPECULATIVE] Intramuscular depot delivery of a stapled peptide SP-RNC would achieve local NMJ enrichment (exploiting the anatomically concentrated mTORC1 activity at motor endplates documented in sarcopenic muscle) without the systemic immunosuppression and metabolic disruption associated with systemic rapamycin, enabling a repair window that...

SENS category: RepleniSENS

Key references: • doi.org/10.1038/s41467-020-18140-1] • doi.org/10.1101/2022.09.29.509997] • doi.org/10.1101/2023.10.03.560722] • doi.org/10.1101/2023.11.07.566067] • doi.org/10.1101/2025.04.15.648965]