Fig. 4: The LCA–TULP3–sirtuin–v-ATPase axis exerts rejuvenating effects.

a, V1E1(3KR) induces oxidative fibre conversion in the muscles of aged mice. Images (left) and quantification (right) of muscle fibre types from WT mice and muscle-specific Ampka knockout (α-MKO) mice with muscle-specific expression of V1E1(3KR) (induced by tamoxifen at 16 months old; see the section ‘Mouse strains’ in the Methods for the procedures for constructing this strain). GAS, gastrocnemius; EDL, extensor digitorum longus; SOL, soleus; TA, tibialis anterior. Scale bars, 50 µm. b, V1E1(3KR) induces increases in muscle NAD⁺ levels in aged mice. Mice were treated as in a, followed by determination of NAD⁺ levels in the gastrocnemius muscle. c,d, V1E1(3KR) promotes muscle strength and running duration in aged mice. Mice were treated as in a, followed by determination of the grip strength (c) and running duration (d). e–g, TULP3(4G) blocks improvement of muscle function by CR in aged mice. Muscle-specific Tulp3 knockout (TULP3-MKO) mice with muscle TULP3(4G) (or WT TULP3 expression (induced by tamoxifen at 16 months old, see validation data in Extended Data Fig. 12i) were subjected to CR for 3.5 months, followed by determination of NAD⁺ levels (e), grip strength (f) and running duration and distance (g). Statistical results are shown as the mean ± s.e.m. Specific numbers of mice used are labelled on each panel. P values (shown on the charts) were calculated using two-way ANOVA followed by Tukey’s test. Experiments were performed three times.

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