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. 2016 Jan:73:23-7.
doi: 10.1016/j.exger.2015.11.010. Epub 2015 Nov 18.

Impaired mitochondrial degradation by autophagy in the skeletal muscle of the aged female interleukin 10 null mouse

Fred Ko  1 , Peter Abadir  2 , Ruth Marx  2 , Reyhan Westbrook  2 , Carol Cooke  3 , Huanle Yang  2 , Jeremy Walston  2
Affiliations

Impaired mitochondrial degradation by autophagy in the skeletal muscle of the aged female interleukin 10 null mouse

Fred Ko et al. Exp Gerontol. 2016 Jan.

Abstract

Mitochondrial dysfunction, chronic inflammation and muscle aging are closely linked. Mitochondrial clearance is a process to dampen inflammation and is a critical pre-requisite to mitobiogenesis. The combined effect of aging and chronic inflammation on mitochondrial degradation by autophagy is understudied. In interleukin 10 null mouse (IL-10(tm/tm)), a rodent model of chronic inflammation, we studied the effects of aging and inflammation on mitochondrial clearance. We show that aging in IL-10(tm/tm) is associated with reduced skeletal muscle mitochondrial death signaling and altered formation of autophagosomes, compared to age-matched C57BL/6 controls. Moreover, skeletal muscles of old IL-10(tm/tm) mice have the highest levels of damaged mitochondria with disrupted mitochondrial ultrastructure and autophagosomes compared to all other groups. These observations highlight the interface between chronic inflammation and aging on altered mitochondrial biology in skeletal muscles.

Keywords: Autophagy; IL-10; MIF; Mitochondria; NIX.

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Figures

Fig 1
Fig 1. Aged and inflamed skeletal muscles show changes in MIF, NIX, and LC3 expression
Western blot analyses of skeletal muscle protein extracts using antibodies against (A) MIF, (B) NIX, and (C) LC3. Actin was used as a loading control. Relative expression was calculated in arbitrary units (AU). (D) A representation of the MIF, NIX, and LC3 Western blots. Data are means ± SEM (n=3–5 animals) *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001.
Fig 2
Fig 2
Altered mitochondrial ultrastructure and autophagosomes with aging and/or inflammation. TEM assessment of autophagosomes (AP) and mitochondrial morphology in quadriceps femoris muscles of female IL-10tm/tm and B6 mice. (A) Photomicrograph demonstrating the presence of an intracellular, vacuolated, double-membrane AP (black arrow, 30,000×) in a longitudinal skeletal muscle section of a 23 months-old IL-10tm/tm mouse. (B) Double-membrane structure (white arrow, 200,000×) surrounding an AP. (C) AP with electron-dense granular inclusions (white arrow heads, 25,000×) located in proximity of clusters of mitochondria (black arrow heads). (D) Mitochondria with normal ultrastructure including intact mitochondrial membranes, cristae, and matrix (black arrow, 80,000×) in the skeletal muscle of a 23 months-old B6 mouse. (E, F) Mitochondria with abnormal structure including disrupted membrane (white arrows), loss of cristae, and matrix dissolution (asterisks) in 23 months-old B6 (E, 100,000×) and IL-10tm/tm (F, 80,000×) mice.
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