Hypothesis

Chronic phonatory stress imposes a persistent siege on vocal fold fibroblasts and myocytes, keeping autophagy constitutively activated as a rationing response. Over time, this sustained demand exhausts the autophagic machinery, shifting the system from adaptive flux to insufficiency. We propose that mechanotransduction via integrin‑FAK signaling suppresses TFEB nuclear translocation, blocking lysosomal biogenesis and thereby uncoupling autophagosome formation from degradation. The resulting accumulation of undegraded cargo drives two parallel pathologies: (1) fibroblast‑mediated dysregulation of extracellular matrix turnover, manifesting as collagen enrichment and elastin/hyaluronan loss, and (2) selective degradation of sarcomeric proteins in the thyroarytenoid muscle, producing atrophy. This unified mechanism explains why ECM densification and muscle wasting co‑occur in presbyphonia and predicts that rescuing lysosomal function will restore autophagic flux and ameliorate both phenotypes.

Testable Predictions

1. Flux measurements – In aged rat vocal folds, LC3‑II accumulation will rise with bafilomycin A1 treatment less than in young tissue, indicating reduced autophagosome‑lysosome fusion.
2. TFEB localization – Immunostaining will show decreased nuclear TFEB in fibroblasts and myocytes from aged versus young folds, correlating with elevated phospho‑FAK levels.
3. Lysosomal rescue – Pharmacological activation of TFEB (e.g., with trehalose) or lysosomal gene overexpression will normalize collagen synthesis, increase elastin/hyaluronan, and preserve thyroarytenoid fiber cross‑sectional area in aged animals.
4. Mechanotransduction blockade – Inhibiting FAK signaling will increase TFEB nuclear entry, enhance autophagic flux, and attenuate both ECM dysregulation and muscle atrophy despite ongoing phonatory load.

Falsifiable Outcome

If lysosomal capacity is not limiting—i.e., TFEB remains nuclear and autophagic flux remains robust in aged vocal folds despite ECM changes and muscle loss—then the proposed insufficiency model is falsified, suggesting alternative drivers for the observed phenotypes.

Mechanistic Insight Beyond Cited Work

While prior studies link ECM to autophagy regulation [5] and describe stress‑induced autophagy as a survival response [1,2], they do not address how chronic mechanical signaling can epigenetically lock the lysosomal program in an off state. We argue that persistent integrin‑FAK signaling activates mTORC1 locally, which phosphorylates and retains TFEB in the cytoplasm, creating a feed‑forward loop where reduced lysosomal output further stresses the autophagy system, forcing the cell to sacrifice structural proteins and matrix components. This positions autophagy insufficiency not as a passive failure but as an actively maintained state driven by mechanosensitive signaling, offering a direct node for therapeutic intervention.