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. 2019 Jul;99(7):1041-1048.
doi: 10.1038/s41374-019-0233-x. Epub 2019 Feb 11.

Association between TDP-43 and mitochondria in inclusion body myositis

Mikayla L Huntley  1 , Ju Gao  1 , Pichet Termsarasab  1 , Luwen Wang  1 , Sophia Zeng  1 , Thananan Thammongkolchai  2 , Ying Liu  3 , Mark L Cohen  4 , Xinglong Wang  5   6
Affiliations

Association between TDP-43 and mitochondria in inclusion body myositis

Mikayla L Huntley et al. Lab Invest. 2019 Jul.

Abstract

Inclusion body myositis (IBM) is the most common cause of primary myopathy in individuals aged 50 years and over, and is pathologically characterized by protein aggregates of p62 and mislocalized cytoplasmic TDP-43, as well as mitochondrial abnormalities in affected muscle fibers. Our recent studies have shown the accumulation of TDP-43 in mitochondria in neurons from patients with amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD), and revealed mitochondria as critical mediators of TDP-43 neurotoxicity. In this study, we investigated the association between mitochondria and TDP-43 in biopsied skeletal muscle samples from IBM patients. We found that IBM pathological markers TDP-43, phosphorylated TDP-43, and p62 all coexisted with intensively stained key subunits of mitochondrial oxidative phosphorylation complexes I-V in the same skeletal muscle fibers of patients with IBM. Further immunoblot analysis showed increased levels of TDP-43, truncated TDP-43, phosphorylated TDP-43, and p62, but decreased levels of key subunits of mitochondrial oxidative phosphorylation complexes I and III in IBM patients compared to aged matched control subjects. This is the first demonstration of the close association of TDP-43 accumulation with mitochondria in degenerating muscle fibers in IBM and this association may contribute to the development of mitochondrial dysfunction and pathological protein aggregates.

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Conflict of interest statement

Disclosure/Conflict of Interest

The authors declare that there is no conflict of interest.

Figures

Figure 1.
Figure 1.
Representative immunocytochemistry of TDP-43, pTDP-43, p62, and OXPHOS key subunits in affected muscle fibers in IBM. Adjacent sections show that the same affected IBM muscle fibers positively stained with TDP-43, pTDP-43, and p62 all exhibit intense mitochondrial staining using the OXPHOS antibody cocktail. In contrast, all age-matched control muscle fibers demonstrate relatively weak staining for all proteins. Cytoplasmic TDP-43 or pTDP-43 accumulation is only noted in IBM fibers.
Figure 2.
Figure 2.
Representative double immunofluorescent staining of pTDP-43 and mitochondria in affected muscle fibers in IBM. The large-field and enlarged images show the colocalization between pTDP-43 and mitochondria in IBM muscle biopsy. The line-scan analysis along the solid white line depicted in the merged large-field image to the left is also shown. Green: pTDP-43; Red: mitochondria (stained by the OXPHOS antibody cocktail); Blue: DAPI.
Figure 3.
Figure 3.
Representative immunoblot analysis and quantification of TDP-43, pTDP-43, p62 and OXPHOS key subunits in the soluble protein pool of affected muscle fibers in IBM. Pathogenic pTDP-43 or truncated TDP-43 were significantly increased in the Triton X-100 soluble fraction derived from biopsied muscle fibers from IBM patients, while complex I and III were significantly reduced (n=10 per group). The levels were adjusted by GAPDH. Data are means ± s.e.m. Statistical analysis was done with student t-test. *P < 0.05, **P < 0.01, ns, not significant.
Figure 4.
Figure 4.
Representative immunoblot analysis and quantification of TDP-43 and pTDP-43 in the insoluble protein pools of affected muscle fibers in IBM. Pathogenic pTDP-43 or truncated TDP-43 were greatly increased in both SDS and urea solubilized skeletal muscle extracts from Triton X-100 insoluble pellets from IBM patients (n=10 per group). Data are means ± s.e.m. Statistical analysis was done with student t-test. *P < 0.05, **P < 0.01.
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