Mitochondrial proteostasis stress in muscle drives a long-range protective response to alleviate dietary obesity independently of ATF4

Qiqi Guo, Zhisheng Xu, Danxia Zhou, Tingting Fu, Wen Wang, Wanping Sun, Liwei Xiao, Lin Liu, Chenyun Ding, Yujing Yin, Zheng Zhou, Zongchao Sun, Yuangang Zhu, Wenjing Zhou, Yuhuan Jia, Jiachen Xue, Yuncong Chen, Xiao-Wei Chen, Hai-Long Piao, Bin Lu, Zhenji Gan, Qiqi Guo, Zhisheng Xu, Danxia Zhou, Tingting Fu, Wen Wang, Wanping Sun, Liwei Xiao, Lin Liu, Chenyun Ding, Yujing Yin, Zheng Zhou, Zongchao Sun, Yuangang Zhu, Wenjing Zhou, Yuhuan Jia, Jiachen Xue, Yuncong Chen, Xiao-Wei Chen, Hai-Long Piao, Bin Lu, Zhenji Gan

Abstract

Mitochondrial quality in skeletal muscle is crucial for maintaining energy homeostasis during metabolic stresses. However, how muscle mitochondrial quality is controlled and its physiological impacts remain unclear. Here, we demonstrate that mitoprotease LONP1 is essential for preserving muscle mitochondrial proteostasis and systemic metabolic homeostasis. Skeletal muscle-specific deletion of Lon protease homolog, mitochondrial (LONP1) impaired mitochondrial protein turnover, leading to muscle mitochondrial proteostasis stress. A benefit of this adaptive response was the complete resistance to diet-induced obesity. These favorable metabolic phenotypes were recapitulated in mice overexpressing LONP1 substrate ΔOTC in muscle mitochondria. Mechanistically, mitochondrial proteostasis imbalance elicits an unfolded protein response (UPRmt) in muscle that acts distally to modulate adipose tissue and liver metabolism. Unexpectedly, contrary to its previously proposed role, ATF4 is dispensable for the long-range protective response of skeletal muscle. Thus, these findings reveal a pivotal role of LONP1-dependent mitochondrial proteostasis in directing muscle UPRmt to regulate systemic metabolism.

Figures

Fig. 1.. Skeletal muscle–specific deletion of LONP1…
Fig. 1.. Skeletal muscle–specific deletion of LONP1 confers resistance to diet-induced obesity and improves insulin sensitivity.
(A) Confocal images of soleus muscle fibers from LONP1 mKO/MitoTimer and Lonp1f/f/MitoTimer mice following chow diet (CD) or HFD feeding. Scale bar, 10 μm. (B) Quantification of MitoTimer red:green ratio normalized (= 1.0) is shown. n = 3 to 6. (C) Body weight at the age of 6 weeks. n = 9 to 13. (D) Increase in body weight following HFD feeding. n = 8 to 13. (E) Body composition measured to determine fat mass. n = 8 to 10. (F) Fat mass plotted as a percentage of body weight. (G) Locomotor activity. n = 7 to 8. (H) Food consumption. n = 7 to 8. Data are expressed as gram consumed per gram of body weight per day. (I and J) Oxygen consumption and carbon dioxide production normalized to body weight. n = 8. (K and L) Fasting glucose and insulin levels. n = 8 to 10. (M and N) Left: Glucose and insulin tolerance test (GTT and ITT). Right: Area under the curve for GTT or ITT is shown. n = 8 to 10. Color legend for the panel: white, WT CD; gray, LONP1 mKO CD; orange, WT HFD; diagonal hatch, LONP1 mKO HFD. Values represent means ± SEM. *P < 0.05 versus corresponding WT controls; #P < 0.05 versus corresponding CD controls. Two-tailed unpaired Student’s t test (C and I to L) or one-way analysis of variance (ANOVA) (B, D to H, M, and N) was performed.
Fig. 2.. Muscle LONP1 regulates the response…
Fig. 2.. Muscle LONP1 regulates the response of adipose tissue and liver to HFD.
(A) Pictures of adipose pads from indicated mice fed CD or HFD. (B) Hematoxylin and eosin (H&E) staining of epididymal WAT (eWAT) and BAT. Scale bar, 50 μm. n = 5 to 9. (C) Masson’s trichrome staining in eWAT. Scale bar, 50 μm. n = 5 to 9. (D) Expression of genes [quantitative reverse transcription polymerase chain reaction (qRT-PCR)] in BAT from indicated mice fed CD or HFD. n = 6. (E) Western blot analysis of BAT from indicated mice. n = 4. (F) Quantification of UCP1/tubulin, NDUFB8/tubulin, TOM20/tubulin, and TIM23/tubulin in BAT from indicated mice fed HFD. n = 4. (G) UCP1 immunohistochemistry (IHC) staining in BAT from indicated mice fed CD or HFD. Scale bar, 50 μm. n = 4 to 5. (H) Mitochondrial respiration rates were determined from BAT of indicated genotypes. Succinate/rotenone (Suc/Rot)–stimulated, adenosine 5′-diphosphate (ADP)–dependent, and antimycin-induced respiration is shown. n = 5 to 8. (I) Expression of genes involved in UPRmt in BAT from indicated mice fed CD or HFD. n = 6. (J) Liver weight. n = 8 to 10. (K) H&E and Oil Red O staining of livers. Scale bar, 50 μm. n = 5 to 6. (L) Liver triglyceride levels. n = 6 to 8. Color legend for the panel: white, WT CD; gray, LONP1 mKO CD; orange, WT HFD; diagonal hatch, LONP1 mKO HFD. Values represent means ± SEM. *P < 0.05 versus corresponding WT controls; #P < 0.05 versus corresponding CD controls. Two-tailed unpaired Student’s t test (D, F, H, and I) or one-way ANOVA (J and L) was performed. AU, arbitrary units.
Fig. 3.. Loss of LONP1 elicits the…
Fig. 3.. Loss of LONP1 elicits the mitochondrial UPR in skeletal muscle.
(A) Electron micrographs of soleus muscle showing intermyofibrillar mitochondria in sections from indicated mice fed CD or HFD. Scale bars, 200 nm. n = 3 to 4. (B and C) Mitochondrial respiration rates were determined on mitochondria isolated from muscles of indicated mice using pyruvate (B) or succinate (C) as substrates. Pyruvate/malate (Py/M)- or Suc/Rot-stimulated respiration is shown. n = 3 to 7. (D) Heatmap analysis of genes differentially regulated in LONP1 mKO muscles. Each group is represented by RNA sequencing (RNA-seq) data from two independent samples generated from muscles of 2- and 6-week-old mice. Red, relative increase in abundance; blue, relative decrease. (E) Gene Ontology (GO) enrichment analysis of genes that were induced early at 2 weeks old and were further enhanced by LONP1 abrogation at 6 weeks old, with top 10 terms shown. The dot size reflects the gene count. (F) Expression of genes (qRT-PCR) related to UPR, amino acid metabolism, one-carbon metabolism, and myokines in muscles from HFD-fed LONP1 mKO mice. n = 6. (G) Serum FGF21 and GDF15 levels. n = 6 to 9. Color legend for the panel: white, WT CD; gray, LONP1 mKO CD; orange, WT HFD; diagonal hatch, LONP1 mKO HFD. Values represent means ± SEM. *P < 0.05 versus corresponding WT controls. Two-tailed unpaired Student’s t test (B, C, and F) or one-way ANOVA (G) was performed.
Fig. 4.. Mitochondria overloaded by unfolded proteins…
Fig. 4.. Mitochondria overloaded by unfolded proteins beyond the LONP1 capacity induce the UPRmt in skeletal muscle.
(A) Mitochondria were isolated from indicated mice and incubated with TPE-MI dye, followed by measurement of fluorescence intensity for 2 hours. n = 6 to 8. (B) Quantification of the maximal fluorescence ratios normalized (= 1.0) to WT controls. n = 6 to 8. (C) Top: Western blot analysis of ΔOTC expression in tissues from indicated mice. Bottom: Western blot analysis performed with mitochondrial and cytosolic fractions isolated from muscles of the indicated mice. (D) Left: Heatmap of differentially expressed genes. RNA-seq data (n = 2 independent) were generated from muscles of 2-week-old indicated mice. Red, relative increase in abundance; blue, relative decrease. Right: GO enrichment analysis of gene transcripts up-regulated in MCK-ΔOTC muscles, with top 10 terms shown. (E and F) GSEA of genes regulated in LONP1-deficient muscles in relation to genes altered in MCK-ΔOTC muscles. Genes regulated by ΔOTC overexpression were ranked by fold difference and expressed on the x axis. This dataset was compared with regulated genes identified in LONP1 mKO muscles. (G) GO enrichment analysis of the muscle-UPRmt gene signature, the core set of genes commonly up-regulated by both ΔOTC overexpression and LONP1 mKO in muscle, with top 10 terms shown. (H) Expression of genes (qRT-PCR) related to UPR, amino acid metabolism, one-carbon metabolism, and myokines in muscles from indicated mice. n = 6. Values represent means ± SEM. *P < 0.05 versus corresponding nontransgenic (NTG) controls. Two-tailed unpaired Student’s t tests were performed.
Fig. 5.. Mitochondrial proteostasis stress in skeletal…
Fig. 5.. Mitochondrial proteostasis stress in skeletal muscle protects against HFD-induced obesity and improves glucose homeostasis.
(A) Growth curves following HFD feeding. n = 12 to 14. (B and C) Oxygen consumption and carbon dioxide production normalized to body weight. n = 7 to 8. (D and E) Fasting glucose and insulin levels. n = 12 to 14. (F and G) GTT and ITT. Inset: Area under the curve for GTT or ITT is shown. n = 12 to 14. (H) H&E staining of eWAT, inguinal WAT (iWAT), and BAT of indicated mice following HFD feeding. Scale bar, 50 μm. n = 7 to 9. (I) Expression of genes (qRT-PCR) in BAT from indicated mice. n = 6. (J) UCP1 IHC staining in BAT. Scale bar, 50 μm. n = 4 to 5. (K) Mitochondrial respiration rates were determined from the BAT of indicated genotypes using pyruvate or succinate as substrates. n = 9 to 11. (L) Expression of genes (qRT-PCR) involved in UPRmt in BAT from indicated mice. n = 6. (M) Pictures of livers from the indicated mice fed HFD. (N) Liver weight. n = 12. (O) H&E and Oil Red O staining of livers. Scale bar, 50 μm. n = 6. (P) Liver triglyceride levels. n = 6 to 9. Color legend for the panel: orange, NTG HFD; diagonal hatch, MCK-ΔOTC HFD. Values represent means ± SEM. *P < 0.05 versus corresponding NTG controls. Two-tailed unpaired Student’s t tests were performed.
Fig. 6.. Mitochondrial proteostasis stress programs local…
Fig. 6.. Mitochondrial proteostasis stress programs local amino acid and one-carbon metabolism in skeletal muscle via the ATF4 transcription factor.
(A) Motif enrichment analysis of the muscle-UPRmt gene signature using i-CisTarget. The table includes the transcription factor gene symbols, consensus binding sites, and their normalized enrichment scores (NES). (B) Left: Genome browser tracks of RNA-seq data were visualized in Integrative Genomics Viewer. Right: Expression of the Atf4 (qRT-PCR) in GC muscle from indicated genotypes. n = 6. (C) Mitochondrial respiration rates were determined on mitochondria isolated from muscles of the indicated mice using pyruvate or succinate as substrates. n = 3 to 5. (D) Expression of genes (qRT-PCR) involved in amino acid and one-carbon metabolism in GC muscles from indicated mice. n = 6. (E) Heatmap analysis of muscle metabolites. Capillary electrophoresis–mass spectrometry–based metabolite analysis was performed with GC muscles from indicated mice. n = 7. Red, relative increase in abundance; blue, relative decrease. ADMA, asymmetric dimethylarginine; NADH, reduced form of nicotinamide adenine dinucleotide. (F) Pathway analysis of ATF4-dependent metabolites using online software MetaboAnalyst 5.0. (G) Amino acid levels in WT, LONP1 mKO, and LONP1/ATF4 DmKO muscles. n = 7. Color legend for the panel: white, WT; gray, LONP1 mKO; orange, LONP1/ATF4 DmKO. Values represent means ± SEM. *P < 0.05 versus WT controls; #P < 0.05 versus LONP1 mKO. One-way ANOVA tests were performed.
Fig. 7.. Mitochondrial proteostasis stress directs a…
Fig. 7.. Mitochondrial proteostasis stress directs a long-range metabolic response independent of ATF4 in skeletal muscle.
(A) Heatmap analysis of genes differentially regulated in muscles from indicated mice. Each group is represented by RNA-seq data from two independent samples generated from muscles from indicated mice. The differentially regulated genes were clustered into four groups, and a color scheme for fold change is provided. Red, relative increase in abundance; blue, relative decrease. (B) GO enrichment analysis of clusters I (ATF4-dependent) and III (ATF4-independent) genes, with top 10 terms shown. (C) Expression of myokines genes (qRT-PCR) in GC muscles from the indicated mice. n = 6. (D) H&E staining of eWAT, iWAT, and BAT of indicated mice. Scale bar, 50 μm. n = 4 to 8. (E) Mitochondrial respiration rates were determined from the BAT of indicated genotypes using pyruvate or succinate as substrates. n = 4 to 10. (F) H&E and Oil Red O staining of livers from indicated mice. Scale bar, 50 μm. n = 4 to 6. (G) Liver triglyceride levels from indicated mice. n = 5 to 7. Color legend for the panel: white, WT; gray, LONP1 mKO; orange, LONP1/ATF4 DmKO. Values represent means ± SEM. *P < 0.05 versus WT controls; #P < 0.05 versus LONP1 mKO. One-way ANOVA tests were performed.
Fig. 8.. Mitochondrial proteostasis stress in skeletal…
Fig. 8.. Mitochondrial proteostasis stress in skeletal muscle directs a long-range metabolic response to alleviate dietary obesity independent of ATF4.
(A) Body weight of indicated mice at the age of 6 weeks. n = 7 to 14. (B) Increase in body weight following HFD feeding. n = 7 to 14. (C) H&E staining of eWAT, iWAT, and BAT of indicated mice. Scale bar, 20 μm. n = 4 to 7. (D) Mitochondrial respiration rates were determined from the BAT of indicated genotypes using pyruvate as substrate. n = 5 to 7. (E) H&E and Oil Red O staining of livers from indicated mice. Scale bar, 20 μm. n = 5 to 10. (F) The schematic depicts the proposed model for the mitochondrial proteostasis stress in skeletal muscle that drives a long-range protective response to alleviate dietary obesity. Color legend for the panel: white, WT HFD; gray, ATF4 mKO HFD; orange, LONP1 mKO HFD; diagonal hatch, LONP1/ATF4 DmKO HFD. Values represent means ± SEM. *P < 0.05 versus WT controls. One-way ANOVA tests were performed.

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