Supplementary material for Hyaluronan 35 prevents endotoxin-mediated dysregulated skeletal muscle proteostasis during ethanol exposure

Day 7 Study day Acclimitization period to liquid diet 50mL Day 1 Start HA35 or PBS gavage Day 6 End HA35 or PBS gavage Day 2 1% EtOH Day 4 2% EtOH Day 5 6% EtOH Day 6 6% EtOH Day 4 Start daily HA35 or PBS gavage Day 6 End daily HA35 or PBS gavage 3d HA35 protocol 6d HA35 protocol PF mice receive amount of control diet equivalent to what mALD mice ate day prior S.Fig 1 A. B. Pair-fed Ethanol-fed Pair-fed Ethanol-fed Short-term (raw/tissue weight) Short-term (normalized) Chronic (raw/tissue weight) Chronic (normalized) 0 50 100 150 0 1 2 3 4 5 Hz 0 50 100 150 Hz Muscle force (N/gm. sample) Muscle force (N/gm. sample) 0 50 100 150 0 2 4 6 8 10 HZ Pair-fed Ethanol-fed Pair-fed Ethanol-fed 0 50 100 150 200 0 50 100 150 0 100 200 300 400 500 HZ Muscle force (N/cm2) Muscle force (N/cm2) ** ** *** *** *** * * ** ** C. 0 20 40 60 ALT IU/L mALDPF - -HA35 3d 6d mALDPF - -HA35 3d 6d * 5101520 2000 4000 6000 8000 10000 Mean connectivity Soft Threshold (power) Mean Connectivity 1 2 3 4 5 678910 12 14 16 18 20 A. C2C12 RNAseq B. Mouse gastrocnemius RNAseq 5101520 0 1000 2000 3000 4000 5000 6000 Mean connectivity Soft Threshold (power) Mean Connectivity 1 2 3 4 5678910 12 14 16 18 20 S.Fig 2 C. C2C12 proteomics D. Mouse gastrocmius proteomics 5101520 0 200 400 600 800 Mean connectivity Soft Threshold (power) Mean Connectivity 1 2 3 4 5 678910 12 14 16 18 20 5101520 0 50 100 150 200 250 Mean connectivity Soft Threshold (power) Mean Connectivity 1 2 3 4 5678910 12 14 16 18 20 A. C2C12 RNAseq B. Mouse gastrocnemius RNAseq S.Fig 3 C. C2C12 proteomics D. Mouse gastrocmius proteomics 5101520 0.0 0.2 0.4 0.6 0.8 Scale independence Soft Threshold (power) Scale Free Topology Model Fit,signed R^2 1 2 3 4 5 678910 12 14 16 18 20 5101520 0.0 0.2 0.4 0.6 0.8 1.0 Scale independence Soft Threshold (power) Scale Free Topology Model Fit,signed R^2 12 34 5 6 7 8 910 12 14 16 18 20 5101520 0.0 0.2 0.4 0.6 0.8 1.0 Scale independence Soft Threshold (power) Scale Free Topology Model Fit,signed R^2 1 2 345 6 78910 12 14 16 18 20 5101520 0.0 0.2 0.4 0.6 0.8 1.0 Scale independence Soft Threshold (power) Scale Free Topology Model Fit,signed R^2 1 2 3 4 5 6 7 8 910 12 14 16 18 20 Myotube proteomics Mouse proteomics Protein Dendrogram Protein Dendrogram Height 0.2 0.4 0.6 0.8 1.0 0.2 0.4 0.6 0.8 1.0 Merged Module Merged Module S.Fig 4 Module−trait relationships −1 −0.5 0 0.5 1 LC3_lipidation Beclin Puromycin ATP Myotube_diameter Complex._1_ETC Complex._2_ETC Complex._3_ETC Complex._4_ETC Complex._5_ETC P1_ADP P1_Glutamate P1_Rot.Sens. P1_Rot.Insensitive MEindianred4 MEbisque4 MEsalmon2 MElightcyan MEsienna4 MEpalevioletred3 MElightsteelblue1 MEpalevioletred2 MEcoral3 MEdarkgrey MElightgreen MEskyblue4 MEthistle2 MEbrown2 MEdarkseagreen3 MEantiquewhite2 MEskyblue MEdarkgreen MEfloralwhite MEdarkorange2 MEpink MEroyalblue MEnavajowhite1 MEthistle1 MEbrown MEdarkolivegreen MEfirebrick4 MEsaddlebrown MEgreen MElavenderblush3 MEmediumpurple3 MEdarkred MEmediumpurple2 MEcoral MEdarkmagenta MEdarkslateblue MEpurple MEblack MEbrown4 MEcoral2 MEorange MElightpink4 MEmagenta −0.69 (0.1) −0.69 (0.1) 0.69 (0.1) 0.69 (0.1) 0.69 (0.1) 0.18 (0.7) 0.75 (0.09) 0.77 (0.08) 0.56 (0.2) 0.79 (0.06) 0.69 (0.1) 0.69 (0.1) 0.69 (0.1) 0.69 (0.1) −0.56 (0.2) −0.56 (0.2) 0.56 (0.2) 0.56 (0.2) 0.56 (0.2) 0.1 (0.8) 0.22 (0.7) 0.6 (0.2) −0.18 (0.7) 0.35 (0.5) 0.56 (0.2) 0.56 (0.2) 0.56 (0.2) 0.56 (0.2) −0.64 (0.2) −0.64 (0.2) 0.64 (0.2) 0.64 (0.2) 0.64 (0.2) 0.1 (0.8) 0.27 (0.6) 0.44 (0.4) 0.15 (0.8) 0.48 (0.3) 0.64 (0.2) 0.64 (0.2) 0.64 (0.2) 0.64 (0.2) 0.016 (1) 0.016 (1) −0.016 (1) −0.016 (1) −0.016 (1) −0.17 (0.7) 0.18 (0.7) 0.4 (0.4) −0.25 (0.6) 0.046 (0.9) −0.016 (1) −0.016 (1) −0.016 (1) −0.016 (1) −0.42 (0.4) −0.42 (0.4) 0.42 (0.4) 0.42 (0.4) 0.42 (0.4) 0.35 (0.5) 0.4 (0.4) 0.7 (0.1) 0.006 (1) 0.32 (0.5) 0.42 (0.4) 0.42 (0.4) 0.42 (0.4) 0.42 (0.4) 0.32 (0.5) 0.32 (0.5) −0.32 (0.5) −0.32 (0.5) −0.32 (0.5) −0.072 (0.9) −0.24 (0.6) 0.036 (0.9) −0.52 (0.3) −0.42 (0.4) −0.32 (0.5) −0.32 (0.5) −0.32 (0.5) −0.32 (0.5) −0.033 (1) −0.033 (1) 0.033 (1) 0.033 (1) 0.033 (1) 0.035 (0.9) −0.37 (0.5) 0.049 (0.9) −0.59 (0.2) −0.33 (0.5) 0.033 (1) 0.033 (1) 0.033 (1) 0.033 (1) 0.56 (0.2) 0.56 (0.2) −0.56 (0.2) −0.56 (0.2) −0.56 (0.2) −0.42 (0.4) −0.7 (0.1) −0.44 (0.4) −0.78 (0.06) −0.76 (0.08) −0.56 (0.2) −0.56 (0.2) −0.56 (0.2) −0.56 (0.2) −0.32 (0.5) −0.32 (0.5) 0.32 (0.5) 0.32 (0.5) 0.32 (0.5) 0.39 (0.4) −0.13 (0.8) 0.43 (0.4) −0.61 (0.2) −0.1 (0.8) 0.32 (0.5) 0.32 (0.5) 0.32 (0.5) 0.32 (0.5) −0.42 (0.4) −0.42 (0.4) 0.42 (0.4) 0.42 (0.4) 0.42 (0.4) 0.59 (0.2) −0.38 (0.5) 0.15 (0.8) −0.6 (0.2) −0.19 (0.7) 0.42 (0.4) 0.42 (0.4) 0.42 (0.4) 0.42 (0.4) −0.085 (0.9) −0.085 (0.9) 0.085 (0.9) 0.085 (0.9) 0.085 (0.9) −0.082 (0.9) −0.32 (0.5) −0.33 (0.5) −0.15 (0.8) −0.072 (0.9) 0.085 (0.9) 0.085 (0.9) 0.085 (0.9) 0.085 (0.9) −0.28 (0.6) −0.28 (0.6) 0.28 (0.6) 0.28 (0.6) 0.28 (0.6) −0.07 (0.9) −0.3 (0.6) −0.0096 (1) −0.43 (0.4) −0.033 (1) 0.28 (0.6) 0.28 (0.6) 0.28 (0.6) 0.28 (0.6) −0.91 (0.01) −0.91 (0.01) 0.91 (0.01) 0.91 (0.01) 0.91 (0.01) 0.65 (0.2) 0.34 (0.5) 0.74 (0.09) −0.014 (1) 0.55 (0.3) 0.91 (0.01) 0.91 (0.01) 0.91 (0.01) 0.91 (0.01) −0.4 (0.4) −0.4 (0.4) 0.4 (0.4) 0.4 (0.4) 0.4 (0.4) 0.14 (0.8) 0.065 (0.9) 0.45 (0.4) −0.37 (0.5) 0.18 (0.7) 0.4 (0.4) 0.4 (0.4) 0.4 (0.4) 0.4 (0.4) −0.38 (0.5) −0.38 (0.5) 0.38 (0.5) 0.38 (0.5) 0.38 (0.5) 0.27 (0.6) 0.017 (1) 0.24 (0.6) −0.21 (0.7) 0.18 (0.7) 0.38 (0.5) 0.38 (0.5) 0.38 (0.5) 0.38 (0.5) −0.0072 (1) −0.0072 (1) 0.0072 (1) 0.0072 (1) 0.0072 (1) 0.33 (0.5) −0.098 (0.9) 0.044 (0.9) −0.27 (0.6) −0.12 (0.8) 0.0072 (1) 0.0072 (1) 0.0072 (1) 0.0072 (1) 0.21 (0.7) 0.21 (0.7) −0.21 (0.7) −0.21 (0.7) −0.21 (0.7) 0.46 (0.4) −0.43 (0.4) −0.18 (0.7) −0.54 (0.3) −0.51 (0.3) −0.21 (0.7) −0.21 (0.7) −0.21 (0.7) −0.21 (0.7) 0.023 (1) 0.023 (1) −0.023 (1) −0.023 (1) −0.023 (1) 0.52 (0.3) −0.63 (0.2) −0.34 (0.5) −0.56 (0.3) −0.52 (0.3) −0.023 (1) −0.023 (1) −0.023 (1) −0.023 (1) −0.26 (0.6) −0.26 (0.6) 0.26 (0.6) 0.26 (0.6) 0.26 (0.6) 0.71 (0.1) −0.049 (0.9) 0.008 (1) 0.1 (0.8) −0.00057 (1) 0.26 (0.6) 0.26 (0.6) 0.26 (0.6) 0.26 (0.6) −0.74 (0.09) −0.74 (0.09) 0.74 (0.09) 0.74 (0.09) 0.74 (0.09) 0.74 (0.09) 0.44 (0.4) 0.45 (0.4) 0.45 (0.4) 0.6 (0.2) 0.74 (0.09) 0.74 (0.09) 0.74 (0.09) 0.74 (0.09) −0.43 (0.4) −0.43 (0.4) 0.43 (0.4) 0.43 (0.4) 0.43 (0.4) 0.63 (0.2) −0.18 (0.7) 0.086 (0.9) −0.26 (0.6) 0.019 (1) 0.43 (0.4) 0.43 (0.4) 0.43 (0.4) 0.43 (0.4) −0.047 (0.9) −0.047 (0.9) 0.047 (0.9) 0.047 (0.9) 0.047 (0.9) 0.33 (0.5) 0.26 (0.6) 0.094 (0.9) 0.44 (0.4) 0.14 (0.8) 0.047 (0.9) 0.047 (0.9) 0.047 (0.9) 0.047 (0.9) 0.21 (0.7) 0.21 (0.7) −0.21 (0.7) −0.21 (0.7) −0.21 (0.7) −0.22 (0.7) 0.077 (0.9) −0.35 (0.5) 0.53 (0.3) 0.051 (0.9) −0.21 (0.7) −0.21 (0.7) −0.21 (0.7) −0.21 (0.7) 0.29 (0.6) 0.29 (0.6) −0.29 (0.6) −0.29 (0.6) −0.29 (0.6) −0.18 (0.7) 0.37 (0.5) −0.15 (0.8) 0.71 (0.1) 0.18 (0.7) −0.29 (0.6) −0.29 (0.6) −0.29 (0.6) −0.29 (0.6) −0.58 (0.2) −0.58 (0.2) 0.58 (0.2) 0.58 (0.2) 0.58 (0.2) 0.42 (0.4) 0.85 (0.03) 0.6 (0.2) 0.91 (0.01) 0.82 (0.04) 0.58 (0.2) 0.58 (0.2) 0.58 (0.2) 0.58 (0.2) 0.04 (0.9) 0.04 (0.9) −0.04 (0.9) −0.04 (0.9) −0.04 (0.9) −0.42 (0.4) 0.47 (0.3) −0.072 (0.9) 0.82 (0.05) 0.45 (0.4) −0.04 (0.9) −0.04 (0.9) −0.04 (0.9) −0.04 (0.9) −0.42 (0.4) −0.42 (0.4) 0.42 (0.4) 0.42 (0.4) 0.42 (0.4) 0.19 (0.7) 0.56 (0.3) 0.19 (0.7) 0.83 (0.04) 0.65 (0.2) 0.42 (0.4) 0.42 (0.4) 0.42 (0.4) 0.42 (0.4) 0.37 (0.5) 0.37 (0.5) −0.37 (0.5) −0.37 (0.5) −0.37 (0.5) −0.33 (0.5) −0.29 (0.6) −0.43 (0.4) −0.19 (0.7) −0.27 (0.6) −0.37 (0.5) −0.37 (0.5) −0.37 (0.5) −0.37 (0.5) 1 (5e−06) 1 (5e−06) −1 (5e−06) −1 (5e−06) −1 (5e−06) −0.74 (0.09) −0.65 (0.2) −0.85 (0.03) −0.4 (0.4) −0.81 (0.05) −1 (5e−06) −1 (5e−06) −1 (5e−06) −1 (5e−06) 0.75 (0.09) 0.75 (0.09) −0.75 (0.09) −0.75 (0.09) −0.75 (0.09) −0.82 (0.05) −0.73 (0.1) −0.77 (0.07) −0.58 (0.2) −0.72 (0.1) −0.75 (0.09) −0.75 (0.09) −0.75 (0.09) −0.75 (0.09) 0.71 (0.1) 0.71 (0.1) −0.71 (0.1) −0.71 (0.1) −0.71 (0.1) −0.67 (0.1) −0.49 (0.3) −0.47 (0.4) −0.57 (0.2) −0.61 (0.2) −0.71 (0.1) −0.71 (0.1) −0.71 (0.1) −0.71 (0.1) −0.067 (0.9) −0.067 (0.9) 0.067 (0.9) 0.067 (0.9) 0.067 (0.9) −0.57 (0.2) −0.036 (0.9) −0.0027 (1) −0.075 (0.9) 0.11 (0.8) 0.067 (0.9) 0.067 (0.9) 0.067 (0.9) 0.067 (0.9) 0.35 (0.5) 0.35 (0.5) −0.35 (0.5) −0.35 (0.5) −0.35 (0.5) −0.62 (0.2) −0.52 (0.3) −0.4 (0.4) −0.49 (0.3) −0.45 (0.4) −0.35 (0.5) −0.35 (0.5) −0.35 (0.5) −0.35 (0.5) 0.79 (0.06) 0.79 (0.06) −0.79 (0.06) −0.79 (0.06) −0.79 (0.06) −0.62 (0.2) −0.82 (0.05) −0.95 (0.003) −0.45 (0.4) −0.81 (0.05) −0.79 (0.06) −0.79 (0.06) −0.79 (0.06) −0.79 (0.06) 0.37 (0.5) 0.37 (0.5) −0.37 (0.5) −0.37 (0.5) −0.37 (0.5) −0.21 (0.7) −0.86 (0.03) −0.76 (0.08) −0.59 (0.2) −0.68 (0.1) −0.37 (0.5) −0.37 (0.5) −0.37 (0.5) −0.37 (0.5) 0.6 (0.2) 0.6 (0.2) −0.6 (0.2) −0.6 (0.2) −0.6 (0.2) −0.76 (0.08) −0.35 (0.5) −0.6 (0.2) −0.031 (1) −0.4 (0.4) −0.6 (0.2) −0.6 (0.2) −0.6 (0.2) −0.6 (0.2) 0.43 (0.4) 0.43 (0.4) −0.43 (0.4) −0.43 (0.4) −0.43 (0.4) −0.78 (0.07) −0.27 (0.6) −0.62 (0.2) 0.093 (0.9) −0.18 (0.7) −0.43 (0.4) −0.43 (0.4) −0.43 (0.4) −0.43 (0.4) 0.44 (0.4) 0.44 (0.4) −0.44 (0.4) −0.44 (0.4) −0.44 (0.4) 0.039 (0.9) −0.61 (0.2) −0.49 (0.3) −0.46 (0.4) −0.68 (0.1) −0.44 (0.4) −0.44 (0.4) −0.44 (0.4) −0.44 (0.4) 0.78 (0.06) 0.78 (0.06) −0.78 (0.06) −0.78 (0.06) −0.78 (0.06) −0.46 (0.4) −0.34 (0.5) −0.58 (0.2) −0.086 (0.9) −0.57 (0.2) −0.78 (0.06) −0.78 (0.06) −0.78 (0.06) −0.78 (0.06) 0.74 (0.09) 0.74 (0.09) −0.74 (0.09) −0.74 (0.09) −0.74 (0.09) −0.21 (0.7) −0.43 (0.4) −0.43 (0.4) −0.43 (0.4) −0.68 (0.1) −0.74 (0.09) −0.74 (0.09) −0.74 (0.09) −0.74 (0.09) 0.03 (1) 0.03 (1) −0.03 (1) −0.03 (1) −0.03 (1) 0.017 (1) 0.68 (0.1) 0.35 (0.5) 0.65 (0.2) 0.44 (0.4) −0.03 (1) −0.03 (1) −0.03 (1) −0.03 (1) 0.69 (0.1) 0.69 (0.1) −0.69 (0.1) −0.69 (0.1) −0.69 (0.1) −0.65 (0.2) −0.013 (1) −0.24 (0.6) −0.019 (1) −0.29 (0.6) −0.69 (0.1) −0.69 (0.1) −0.69 (0.1) −0.69 (0.1) 0.43 (0.4) 0.43 (0.4) −0.43 (0.4) −0.43 (0.4) −0.43 (0.4) −0.19 (0.7) 0.071 (0.9) −0.0083 (1) −0.086 (0.9) −0.17 (0.7) −0.43 (0.4) −0.43 (0.4) −0.43 (0.4) −0.43 (0.4) A. C2C12 RNAseq S.Fig 5 B. Mouse gastrocnemius RNAseq S.Fig 5 Module−trait relationships −1 −0.5 0 MEpalevioletred3 MEthistle MEindianred4 MEdarkgrey MEthistle4 MEmediumpurple2 MEplum1 MEyellow MEcoral MEdarkslateblue MEblue3 MEcoral2 MEorangered4 MEwhitesmoke MEhoneydew1 MEred MElavenderblush2 MElavenderblush3 MEpink3 MEbrown MEfirebrick3 MEdarkseagreen1 MElightsteelblue MEblue MElightblue3 MEchocolate3 MEfloralwhite MEgreen3 MEsienna2 MEgreenyellow MEhoneydew MEdarkviolet MEtan3 MEsienna3 MEyellow3 MEskyblue4 MEdarkorange2 MElightsteelblue1 MElightblue4 MEblueviolet MEchocolate4 MEmaroon MEorangered3 MEgreen4 MEtan4 MElavenderblush MEmagenta3 MEsienna1 −0.22 (0.6) −0.26 (0.5) −0.36 (0.3) −0.03 (0.9) −0.28 (0.5) −0.11 (0.8) −0.51 (0.2) −0.36 (0.3) −0.09 (0.8) −0.21 (0.6) −0.0021 (1) −0.015 (1) 0.0082 (1) −0.1 (0.8) 0.53 (0.1) 0.23 (0.5) −0.11 (0.8) 0.49 (0.2) 0.66 (0.05) −0.19 (0.6) 0.068 (0.9) 0.62 (0.08) 0.14 (0.7) 0.3 (0.4) 0.74 (0.02) −0.17 (0.7) 0.78 (0.01) 0.9 (0.001) −0.1 (0.8) 0.61 (0.08) 0.51 (0.2) −0.43 (0.3) 0.58 (0.1) 0.084 (0.8) 0.26 (0.5) 0.44 (0.2) 0.27 (0.5) −0.26 (0.5) 0.64 (0.06) −0.03 (0.9) 0.28 (0.5) 0.4 (0.3) 0.4 (0.3) 0.23 (0.6) 0.48 (0.2) 0.66 (0.05) 0.09 (0.8) 0.73 (0.03) 0.059 (0.9) 0.23 (0.5) −0.28 (0.5) −0.38 (0.3) 0.35 (0.4) −0.39 (0.3) −0.19 (0.6) 0.23 (0.6) 0.41 (0.3) −0.41 (0.3) −0.26 (0.5) −0.0045 (1) −0.47 (0.2) −0.28 (0.5) −0.055 (0.9) 0.12 (0.8) −0.22 (0.6) 0.088 (0.8) 0.29 (0.5) 0.036 (0.9) 0.37 (0.3) −0.25 (0.5) −0.18 (0.7) −0.38 (0.3) −0.32 (0.4) −0.18 (0.6) −0.53 (0.1) −0.052 (0.9) 0.39 (0.3) −0.22 (0.6) 0.39 (0.3) −0.19 (0.6) −0.15 (0.7) −0.19 (0.6) 0.13 (0.7) −0.25 (0.5) −0.072 (0.9) −0.18 (0.6) −0.0037 (1) −0.44 (0.2) −0.16 (0.7) −0.17 (0.7) −0.75 (0.02) −0.11 (0.8) −0.3 (0.4) −0.015 (1) 0.35 (0.4) −0.23 (0.6) −0.25 (0.5) 0.38 (0.3) −0.34 (0.4) −0.55 (0.1) 0.059 (0.9) −0.42 (0.3) 0.077 (0.8) 0.3 (0.4) 0.14 (0.7) −0.026 (0.9) 0.19 (0.6) 0.16 (0.7) −0.15 (0.7) 0.68 (0.04) −0.058 (0.9) −0.49 (0.2) 0.32 (0.4) −0.13 (0.7) −0.44 (0.2) 0.36 (0.3) −0.058 (0.9) −0.17 (0.7) 0.85 (0.004) −0.3 (0.4) −0.37 (0.3) 0.35 (0.4) −0.48 (0.2) −0.21 (0.6) 0.87 (0.002) −0.076 (0.8) −0.37 (0.3) 0.52 (0.1) 0.12 (0.8) 0.042 (0.9) 0.56 (0.1) 0.63 (0.07) 0.08 (0.8) 0.7 (0.03) 0.49 (0.2) 0.55 (0.1) 0.5 (0.2) 0.57 (0.1) 0.52 (0.2) 0.82 (0.007) 0.39 (0.3) 0.1 (0.8) 0.72 (0.03) 0.29 (0.4) Module−trait relationships 0 0.5 1 MEmediumpurple MEaliceblue MEdarkolivegreen2 MEdarkseagreen3 MEfirebrick4 MEpink4 MEdarkorange MEbisque4 MEcyan MEthistle3 MEindianred2 MEplum MEwhite MEdarkgreen MEpalevioletred MEpalevioletred2 MEplum2 MEcornflowerblue MEmediumorchid MElightcoral MEorangered1 MEdarkmagenta MEbrown4 MEplum4 MEnavajowhite2 MElightcyan1 MEbrown2 MEnavajowhite3 MEantiquewhite1 MElightpink1 MElightslateblue MEblack MEindianred3 MEorangered MEcoral3 MEmagenta2 MEgrey60 MElightpink3 MElightgreen MEturquoise MEsteelblue MEdeeppink1 MEdarkseagreen4 MEnavajowhite1 MElavenderblush1 MEskyblue2 0.1 (0.8) 0.35 (0.4) −0.12 (0.8) −0.23 (0.5) 0.44 (0.2) −0.52 (0.1) −0.47 (0.2) 0.42 (0.3) −0.49 (0.2) −0.44 (0.2) 0.16 (0.7) −0.72 (0.03) −0.79 (0.01) −0.065 (0.9) −0.82 (0.006) −0.41 (0.3) −0.37 (0.3) −0.57 (0.1) −0.14 (0.7) −0.047 (0.9) −0.54 (0.1) −0.6 (0.09) 0.11 (0.8) −0.62 (0.08) −0.24 (0.5) −0.34 (0.4) −0.52 (0.2) 0.29 (0.4) 0.061 (0.9) −0.2 (0.6) −0.24 (0.5) −0.28 (0.5) −0.33 (0.4) −0.18 (0.6) −0.2 (0.6) −0.48 (0.2) 0.044 (0.9) −0.25 (0.5) −0.39 (0.3) −0.091 (0.8) −0.08 (0.8) −0.24 (0.5) −0.19 (0.6) 0.47 (0.2) −0.3 (0.4) −0.044 (0.9) 0.44 (0.2) −0.38 (0.3) 0.33 (0.4) 0.31 (0.4) 0.16 (0.7) −0.55 (0.1) −0.17 (0.7) −0.49 (0.2) −0.58 (0.1) −0.26 (0.5) −0.43 (0.3) −0.5 (0.2) −0.27 (0.5) −0.24 (0.5) −0.31 (0.4) −0.29 (0.5) −0.085 (0.8) −0.32 (0.4) −0.2 (0.6) −0.12 (0.8) 0.25 (0.5) −0.23 (0.6) 0.63 (0.07) 0.13 (0.7) −0.36 (0.3) 0.47 (0.2) 0.21 (0.6) −0.56 (0.1) 0.15 (0.7) 0.31 (0.4) −0.39 (0.3) −0.15 (0.7) 0.43 (0.3) −0.43 (0.2) 0.4 (0.3) 0.36 (0.3) −0.18 (0.6) 0.098 (0.8) 0.4 (0.3) −0.18 (0.6) −0.2 (0.6) 0.33 (0.4) 0.17 (0.7) 0.0078 (1) 0.24 (0.5) −0.14 (0.7) −0.19 (0.6) 0.25 (0.5) −0.1 (0.8) 0.086 (0.8) 0.55 (0.1) 0.4 (0.3) 0.31 (0.4) 0.15 (0.7) 0.47 (0.2) −0.26 (0.5) 0.24 (0.5) −0.052 (0.9) −0.066 (0.9) 0.11 (0.8) −0.27 (0.5) 0.068 (0.9) 0.8 (0.01) −0.045 (0.9) 0.31 (0.4) 0.69 (0.04) 0.02 (1) 0.14 (0.7) 0.19 (0.6) −0.28 (0.5) 0.28 (0.5) −0.39 (0.3) −0.11 (0.8) −0.16 (0.7) 0.31 (0.4) −0.23 (0.6) 0.54 (0.1) 0.19 (0.6) −0.00099 (1) 0.72 (0.03) 0.37 (0.3) −0.12 (0.7) 0.9 (8e−04) −0.088 (0.8) −0.21 (0.6) 0.57 (0.1) −0.31 (0.4) −0.16 (0.7) 0.48 (0.2) −0.012 (1) −0.43 (0.2) 0.54 (0.1) Gastroc. TA Heart Gastroc. TA Heart S.Fig 5 C. C2C12 proteomics Module−trait relationships −1 −0.5 00.51 LC3_lipidation Beclin Puromycin ATP Myotube_diameter Complex._1_ETC Complex._2_ETC Complex._3_ETC Complex._4_ETC Complex._5_ETC P1_ADP P1_Glutamate P1_Rot.Sens. P1_Rot.Insensitive MEgreen MEbrown MEgrey60 MEmidnightblue MElightcyan MElightyellow MEsalmon MEdarkgreen MEblue MEgreenyellow MEpink MEdarkgrey MEorange MEblack MEturquoise MEdarkturquoise MEtan MEroyalblue MEyellow MElightgreen MEdarkred MEcyan MEred −0.44 (0.4) −0.44 (0.4) 0.44 (0.4) 0.44 (0.4) 0.44 (0.4) 0.6 (0.2) −0.19 (0.7) 0.092 (0.9) −0.28 (0.6) 0.026 (1) 0.44 (0.4) 0.44 (0.4) 0.44 (0.4) 0.44 (0.4) 0.44 (0.4) 0.44 (0.4) −0.44 (0.4) −0.44 (0.4) −0.44 (0.4) −0.79 (0.06) −0.33 (0.5) −0.61 (0.2) −0.0052 (1) −0.23 (0.7) −0.44 (0.4) −0.44 (0.4) −0.44 (0.4) −0.44 (0.4) 0.21 (0.7) 0.21 (0.7) −0.21 (0.7) −0.21 (0.7) −0.21 (0.7) 0.074 (0.9) −0.74 (0.09) −0.65 (0.2) −0.47 (0.3) −0.56 (0.2) −0.21 (0.7) −0.21 (0.7) −0.21 (0.7) −0.21 (0.7) 0.2 (0.7) 0.2 (0.7) −0.2 (0.7) −0.2 (0.7) −0.2 (0.7) −0.3 (0.6) −0.75 (0.08) −0.55 (0.3) −0.64 (0.2) −0.53 (0.3) −0.2 (0.7) −0.2 (0.7) −0.2 (0.7) −0.2 (0.7) 0.16 (0.8) 0.16 (0.8) −0.16 (0.8) −0.16 (0.8) −0.16 (0.8) −0.4 (0.4) 0.32 (0.5) −0.21 (0.7) 0.74 (0.1) 0.28 (0.6) −0.16 (0.8) −0.16 (0.8) −0.16 (0.8) −0.16 (0.8) −0.2 (0.7) −0.2 (0.7) 0.2 (0.7) 0.2 (0.7) 0.2 (0.7) −0.21 (0.7) 0.23 (0.7) 0.18 (0.7) 0.28 (0.6) 0.28 (0.6) 0.2 (0.7) 0.2 (0.7) 0.2 (0.7) 0.2 (0.7) −0.4 (0.4) −0.4 (0.4) 0.4 (0.4) 0.4 (0.4) 0.4 (0.4) −0.19 (0.7) 0.59 (0.2) 0.33 (0.5) 0.71 (0.1) 0.67 (0.1) 0.4 (0.4) 0.4 (0.4) 0.4 (0.4) 0.4 (0.4) −0.73 (0.1) −0.73 (0.1) 0.73 (0.1) 0.73 (0.1) 0.73 (0.1) 0.6 (0.2) 0.59 (0.2) 0.46 (0.4) 0.69 (0.1) 0.73 (0.1) 0.73 (0.1) 0.73 (0.1) 0.73 (0.1) 0.73 (0.1) −0.55 (0.3) −0.55 (0.3) 0.55 (0.3) 0.55 (0.3) 0.55 (0.3) 0.36 (0.5) 0.89 (0.02) 0.61 (0.2) 0.93 (0.007) 0.83 (0.04) 0.55 (0.3) 0.55 (0.3) 0.55 (0.3) 0.55 (0.3) −0.61 (0.2) −0.61 (0.2) 0.61 (0.2) 0.61 (0.2) 0.61 (0.2) 0.28 (0.6) 0.8 (0.06) 0.78 (0.07) 0.62 (0.2) 0.76 (0.08) 0.61 (0.2) 0.61 (0.2) 0.61 (0.2) 0.61 (0.2) −0.37 (0.5) −0.37 (0.5) 0.37 (0.5) 0.37 (0.5) 0.37 (0.5) −0.065 (0.9) 0.13 (0.8) 0.48 (0.3) −0.25 (0.6) 0.21 (0.7) 0.37 (0.5) 0.37 (0.5) 0.37 (0.5) 0.37 (0.5) −0.64 (0.2) −0.64 (0.2) 0.64 (0.2) 0.64 (0.2) 0.64 (0.2) 0.78 (0.07) 0.12 (0.8) 0.45 (0.4) −0.018 (1) 0.24 (0.7) 0.64 (0.2) 0.64 (0.2) 0.64 (0.2) 0.64 (0.2) −0.26 (0.6) −0.26 (0.6) 0.26 (0.6) 0.26 (0.6) 0.26 (0.6) 0.43 (0.4) −0.49 (0.3) 0.01 (1) −0.66 (0.2) −0.33 (0.5) 0.26 (0.6) 0.26 (0.6) 0.26 (0.6) 0.26 (0.6) 0.11 (0.8) 0.11 (0.8) −0.11 (0.8) −0.11 (0.8) −0.11 (0.8) −0.087 (0.9) −0.42 (0.4) −0.094 (0.9) −0.54 (0.3) −0.4 (0.4) −0.11 (0.8) −0.11 (0.8) −0.11 (0.8) −0.11 (0.8) 0.48 (0.3) 0.48 (0.3) −0.48 (0.3) −0.48 (0.3) −0.48 (0.3) 0.013 (1) −0.61 (0.2) −0.49 (0.3) −0.49 (0.3) −0.7 (0.1) −0.48 (0.3) −0.48 (0.3) −0.48 (0.3) −0.48 (0.3) 0.81 (0.05) 0.81 (0.05) −0.81 (0.05) −0.81 (0.05) −0.81 (0.05) −0.58 (0.2) −0.19 (0.7) −0.63 (0.2) 0.18 (0.7) −0.41 (0.4) −0.81 (0.05) −0.81 (0.05) −0.81 (0.05) −0.81 (0.05) 0.88 (0.02) 0.88 (0.02) −0.88 (0.02) −0.88 (0.02) −0.88 (0.02) −0.66 (0.2) −0.76 (0.08) −0.95 (0.003) −0.38 (0.5) −0.81 (0.05) −0.88 (0.02) −0.88 (0.02) −0.88 (0.02) −0.88 (0.02) 0.057 (0.9) 0.057 (0.9) −0.057 (0.9) −0.057 (0.9) −0.057 (0.9) −0.27 (0.6) 0.13 (0.8) 0.32 (0.5) −0.27 (0.6) 0.023 (1) −0.057 (0.9) −0.057 (0.9) −0.057 (0.9) −0.057 (0.9) 0.44 (0.4) 0.44 (0.4) −0.44 (0.4) −0.44 (0.4) −0.44 (0.4) −0.25 (0.6) 0.085 (0.9) −0.011 (1) −0.068 (0.9) −0.16 (0.8) −0.44 (0.4) −0.44 (0.4) −0.44 (0.4) −0.44 (0.4) −0.051 (0.9) −0.051 (0.9) 0.051 (0.9) 0.051 (0.9) 0.051 (0.9) 0.081 (0.9) 0.3 (0.6) 0.39 (0.4) 0.11 (0.8) 0.12 (0.8) 0.051 (0.9) 0.051 (0.9) 0.051 (0.9) 0.051 (0.9) 0.34 (0.5) 0.34 (0.5) −0.34 (0.5) −0.34 (0.5) −0.34 (0.5) 0.16 (0.8) 0.093 (0.9) −0.037 (0.9) 0.13 (0.8) −0.18 (0.7) −0.34 (0.5) −0.34 (0.5) −0.34 (0.5) −0.34 (0.5) 0.74 (0.09) 0.74 (0.09) −0.74 (0.09) −0.74 (0.09) −0.74 (0.09) −0.22 (0.7) −0.45 (0.4) −0.43 (0.4) −0.45 (0.4) −0.7 (0.1) −0.74 (0.09) −0.74 (0.09) −0.74 (0.09) −0.74 (0.09) 0.39 (0.4) 0.39 (0.4) −0.39 (0.4) −0.39 (0.4) −0.39 (0.4) −0.14 (0.8) −0.36 (0.5) −0.064 (0.9) −0.63 (0.2) −0.53 (0.3) −0.39 (0.4) −0.39 (0.4) −0.39 (0.4) −0.39 (0.4) Module−trait relationships −1 −0.5 0 0.5 1 TA Gastroc. Inital Body Weight Final Body Weight MEyellow MEred MEbrown MEturquoise MEblack MEblue MEgreen MEgrey 0.88 (0.004) 0.37 (0.4) −0.044 (0.9) −0.31 (0.5) 0.21 (0.6) 0.37 (0.4) 0.12 (0.8) 0.2 (0.6) −0.2 (0.6) 0.15 (0.7) −0.048 (0.9) 0.52 (0.2) 0.002 (1) 0.3 (0.5) −0.38 (0.4) −0.0026 (1) −0.28 (0.5) −0.62 (0.1) −0.41 (0.3) −0.55 (0.2) −0.41 (0.3) 0.2 (0.6) 0.64 (0.09) 0.16 (0.7) 0.058 (0.9) 0.24 (0.6) −0.33 (0.4) −0.32 (0.4) −0.42 (0.3) −0.62 (0.1) 0.12 (0.8) 0.14 (0.7) S.Fig 5 D. C2C12 RNAseq GO:BP Cellular Stress C2C12 Proteomics GO:BP Cellular Stress hiPSC RNAseq GO:BP Cellular Stress hiPSC Proteomics GO:BP Cellular Stress UnT 6hEtOH UnT 6hEtOH UnT 6h EtOH UnT 6h EtOH Mif Ube2n Prpf19 Rad21 Nploc4 Park7 Bax Opa1 Rpl26 Flot1 Pdia3 Rsl1d1 Hsp90b1 Mybbp1a Sfpq S.Fig 6