Fig. 4. GDF15 increases calcium futile cycling in skeletal muscle.

a, GDF15 increases noradrenaline in tibialis anterior (TA) muscle. Data are mean ± s.e.m. n = 13 (vehicle), n = 10 (GDF15), n = 9 (pair-fed) mice. P values were calculated using one-way ANOVA with Tukey’s multiple-comparison test. b, Heatmap of the sample-to-sample distances for TA muscle. n = 5 mice per group, except for the GDF15 group, for which n = 6 mice. c, GO annotation between GDF15 and pair-fed groups. The adjusted P value (P_adj) was calculated using the Benjamini–Hochberg method. d, Relative gene expression in muscle. Data are mean ± s.e.m. n = 9 (WT, vehicle; and WT, GDF15), n = 10 (WT, pair-fed) and n = 4 (KO, pair-fed; and KO, GDF15) mice. P values were calculated using two-way ANOVA with Tukey’s multiple-comparison test. a.u., arbitrary units. e, Fatty acid oxidation in soleus muscle. Data are mean ± s.e.m. n = 7 mice per group. P values were calculated using two-sided unpaired t-tests. DPM, disintegrations per minute. f, Force–frequency curve of EDL muscles. Data are mean ± s.e.m. n = 4 mice per group. P values were calculated using two-way ANOVA with Tukey’s multiple-comparison test. g, Calculated calcium (Ca²⁺)-derived ADP in permeabilized fibres from red skeletal muscle. Data are mean ± s.e.m. n = 6 mice per group, except for the GDF15 group, for which n = 5 mice. P values were calculated using one-way ANOVA with Tukey’s multiple-comparison test (Supplementary Fig. 5). Schematic of the SERCA efficiency. P_i, inorganic phosphate. h, Real-time trace from a single soleus respiration experiment (n = 1 mouse per group) showing the experimental protocol to measure basal, caffeine-stimulated (CAF; 3 mM) and Ca²⁺-independent (10 μM dantrolene (DAN)) respiration (JO₂). I, Ca²⁺-dependent JO₂ (CAF-DAN) calculated from Extended Data Fig. 10o. Data are mean ± s.e.m. n = 8 mice per group. P values were calculated using two-sided unpaired t-tests.

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