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. 2024 Jun 27;25(13):7060.
doi: 10.3390/ijms25137060.

Cancerous Conditions Accelerate the Aging of Skeletal Muscle via Mitochondrial DNA Damage

Yi Luo  1   2 , Rina Fujiwara-Tani  1 , Isao Kawahara  1 , Kei Goto  1 , Shota Nukaga  1 , Ryoichi Nishida  1 , Chie Nakashima  1 , Takamitsu Sasaki  1 , Yoshihiro Miyagawa  1 , Ruiko Ogata  1 , Kiyomu Fujii  1 , Hitoshi Ohmori  1 , Hiroki Kuniyasu  1
Affiliations

Cancerous Conditions Accelerate the Aging of Skeletal Muscle via Mitochondrial DNA Damage

Yi Luo et al. Int J Mol Sci. .

Abstract

Skeletal muscle aging and sarcopenia result in similar changes in the levels of aging markers. However, few studies have examined cancer sarcopenia from the perspective of aging. Therefore, this study investigated aging in cancer sarcopenia and explored its causes in vitro and in vivo. In mouse aging, in vitro cachexia, and mouse cachexia models, skeletal muscles showed similar changes in aging markers including oxidative stress, fibrosis, reduced muscle differentiation potential, and telomere shortening. Furthermore, examination of mitochondrial DNA from skeletal muscle revealed a 5 kb deletion in the major arc; truncation of complexes I, IV, and V in the electron transport chain; and reduced oxidative phosphorylation (OXPHOS). The mouse cachexia model demonstrated high levels of high-mobility group box-1 (HMGB1) and tumor necrosis factor-α (TNFα) in cancer ascites. Continuous administration of neutralizing antibodies against HMGB1 and TNFα in this model reduced oxidative stress and abrogated mitochondrial DNA deletion. These results suggest that in cancer sarcopenia, mitochondrial oxidative stress caused by inflammatory cytokines leads to mitochondrial DNA damage, which in turn leads to decreased OXPHOS and the promotion of aging.

Keywords: aging; cancer sarcopenia; mitochondria; mitochondrial DNA.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Alterations of cell kinetics and maturation in the in vitro cachexia model. C2C12 cells were treated with a medium containing cancerous ascites (20% v/v). The medium was changed to ascites-supplemented medium every two days. (A) Cell growth. (B) Apoptotic cells. (C) Number of cells showing cell surface labeling at 144 h. (D) Cell turnover (%) calculated as the unlabeled cell number/total cell number. (E,F) Protein levels of MYH8 and PAX7. * Error bars: standard deviation from three independent trials. Statistical differences were calculated using analysis of variance (ANOVA) with Bonferroni correction. C, control; CX, in vitro cachexia model; MC, medium change; MYH8, myosin heavy chain-8; PAX7, paired box protein-7.
Figure 2
Figure 2
Mitochondrial alterations in the in vitro cachexia model. C2C12 cells were treated with medium containing cancerous ascites (20% v/v). The medium was changed to ascites-supplemented medium every two days. (A) MtVol. (B) MtROS. (C) MMP. (D) Mitophagy. (A–D) Insert, fluorescence images of C 144 h and CX 144 h. Scale bar 50 μm. (E) Labeled mitochondria at 144 h. Mitochondria were labeled by MtGrn at 0 h and relabeled by MtDR at 144 h. (F) Mitochondrial turnover (%) calculated by MtDR+/(MtGrn+ + MtDR+). (G) Mitochondrial respiration. (H) OXPHOS parameters. (I) Mitochondrial DNA alterations. Mitochondrial major arc DNA was amplified using PCR. 10 kb, which is considered a normal-sized band. (J) Protein levels of the ETC complexes. * Error bars: standard deviation from three independent trials. Statistical differences were calculated using analysis of variance (ANOVA) with Bonferroni correction. C, control; CX, in vitro cachexia model; MtVol, mitochondrial volume; MtROS, mitochondrial reactive oxygen species; MMP, mitochondrial membrane potential; MtGrn, mitogreen; MtDR, mito deep red; OCR, oxygen consumption ratio; OXPHOS, oxidative phosphorylation; PCR, polymerase chain reaction; ETC, electron transport chain; C-I, complex I; C-III, complex III; C-IV, complex IV; C-V, complex V.
Figure 3
Figure 3
Mitochondrial changes in the skeletal muscle of a mouse cachexia model. (A) Concentrations of HMGB1 and TNFα in ascites from CX mice used for peritoneal lavage in NT mice. (B) Levels of 4HNE, and protein levels of PINK1 and Parkin in C2C12 cells treated with HMGB1 (50 μg/mL). (C) Mitochondrial DNA alterations in the mouse cachexia model. Mice in the αHMGB1 + αTNFα group were injected with αHMGB1 (0.5 μg/mouse) and αTNFα (0.5 μg/mouse) intraperitoneally three times weekly. Mitochondrial major arc DNA was amplified by PCR. 10 kb, normal-sized band. * Error bars: standard deviation from three independent trials or five mice. Statistical differences were calculated using analysis of variance with the Bonferroni correction. C, control; NT, no tumor; CX, cachexia model; 4HNE, 4-hydroxynonenal; PINK1, PTEN-induced putative kinase 1; αHMGB1, anti-HMGB1 antibody; αTNFα, anti-mouse TNFα antibody; PCR, polymerase chain reaction.
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