IF a sequential-then-concurrent dual-agent regimen — oral miglustat (approximately 100 mg/kg/day in mouse dose equivalent, the established SRT dose from Gaucher/Niemann-Pick pharmacology) administered for 4 weeks prior to and throughout intravenous avalglucosidase alfa (40 mg/kg biweekly, the clinical dose with ~15-fold enhanced bis-M6P/CI-MPR affinity versus alglucosidase alfa) is administered to aged wild-type C57BL/6J male mice (22–24 months), targeting skeletal muscle lysosomes,

THEN a statistically significant reduction (≥40%) in intralysosomal glycogen content and glucosylceramide accumulation in hindlimb skeletal muscle (gastrocnemius and tibialis anterior), accompanied by restoration of lysosomal acidification (luminal pH ≤ 4.8, measured by LysoSensor ratiometric imaging), improved autophagic flux (reduced p62/SQSTM1 and LC3-II accumulation), and measurable reduction in lipofuscin autofluorescence, compared to age-matched vehicle controls and single-agent arms, will be observed within 8 weeks of treatment initiation,

BECAUSE the following mechanistic chain, operating in aged skeletal muscle, makes this synergy causally necessary rather than merely additive:

1. Aged wild-type skeletal muscle accumulates glucosylceramide (GlcCer) as a consequence of progressive decline in lysosomal hydrolase efficiency, creating a secondary storage phenotype analogous to mild Gaucher disease (GlcCer accumulates in aged lysosomes, impairing membrane fluidity and autophagosome-lysosome fusion)(Trayssac et al., Journal of Gerontology, 2018, as cited in the Evidence Set).
2. Elevated intralysosomal GlcCer alters lysosomal membrane lipid composition, impairing the vacuolar H⁺-ATPase (V-ATPase) proton pump efficiency and elevating lysosomal pH above the optimal range for acid hydrolases; this alkalinization reduces Cathepsin D and L activity, stalling the degradation of all lysosomal cargo including glycogen and ubiquitinated protein aggregates (V-ATPase dysfunction elevates lysosomal pH in aged muscle)(Colacurcio & Nixon, Ageing Research Reviews, 2016, as cited in the Evidence Set; Lloyd-Evans et al., Nature Medicine, as cited in the Evidence Set).
3. [SPECULATIVE] This GlcCer-mediated lysosomal alkalinization constitutes a rate-limiting upstream bottleneck for glycogen clearance in aged muscle: even endogenous GAA activity is insufficient to degrade the accumulating age-related glycogen because the enzymatic optima (pH ~4.5) are not met. Miglustat's GCS inhibition therefore does not merely reduce one substrate — it restores the pH permissive environment required for all downstream acid hydrolase activity (Platt et al., Nat Rev Drug Discov, 2018, as cited in the Evidence Set).
4. Miglustat's pharmacological chaperone action stabilizes avalglucosidase alfa at neutral blood pH (preventing denaturation during circulation), extending circulatory half-life and increasing total enzyme delivered to skeletal muscle tissue (miglustat acts as pharma...

SENS category: LysoSENS