Wiesner 2018 MiPschool Tromso E1
Event: MiPschool Tromso-Bergen 2018
During aging, skeletal muscle accumulates mitochondrial DNA (mtDNA) deletions, leading to severe mitochondrial dysfunction in individual muscle segments. It is unclear if and how such a mosaic plays a role in the development of age-related sarcopenia and muscle weakness. To study this, we generated mice with accelerated accumulation of mtDNA deletions specifically in muscle by expressing a dominant-negative variant of the mitochondrial TWINKLE helicase (R26-K320E-TwinkleloxP/+1,2 x MLC1f-Cre: K320E-Twinkleskm). Mice showed age-dependent accumulation of mtDNA deletions (8 -15 fold) and a concomitant increase in the proportion of cytochrome c oxidase deficient fibers, especially in fast-glycolytic, type IIb fiber-rich muscles like tibialis anterior and gastrocnemius (>10% in cross-sections at 24 months), while type I fiber-rich soleus muscle was spared. This is reminiscent of human muscle at old age and in patients with mitochondrial diseases. Despite this obviously severe mitochondrial myopathy, no signs of motor impairment could be observed, neither in vivo nor ex vivo, emphasizing the important involvement of other contributors such as motoneuron and muscle stem cell defects in sarcopenia. RNAseq data confirm the previously described induction of the FGF21 and Mthfd2 genes, but also showed remodeling of the AMPK, cAMP, MAPK, hypoxia and insulin signaling pathways. These changes, together with upregulation of amino acid transport, amino acid, protein and glycogen biosynthetic processes strongly suggest a generally increased turnover. Analysis of LC3, p62 and Lamp1 in situ shows that type I fiber-rich muscles have a higher autophagic and mitophagic rate than type IIb fiber-rich gastrocnemius and tibialis anterior, which may transiently protect the affected myofibers from the detrimental effects of increased accumulation of mtDNA deletions.
Kimoloi SK(1), Pla-Martin D(1), Baris OR(1), Wiesner RJ(1,2)
- Center Physiology Pathophysiology
- Cologne Excellence Cluster Cellular Stress Responses Ageing-associated Diseases (CECAD); Univ Köln, Germany
- Baris OR, Ederer S, Neuhaus JF, von Kleist-Retzow JC, Wunderlich CM, Pal M, Wunderlich FT, Peeva V, Zsurka G, Kunz WS, Hickethier T, Bunck AC, Stöckigt F, Schrickel JW, Wiesner RJ (2015) Mosaic deficiency in mitochondrial oxidative metabolism promotes cardiac arrhythmia during aging. Cell Metab 21:667-77.
- Weiland D, Brachvogel B, Hornig-Do HT, Neuhaus JFG, Holzer T, Tobin DJ, Niessen CM, Wiesner RJ, Baris OR (2018) Imbalance of mitochondrial respiratory chain complexes in the epidermis induces severe skin inflammation. J Invest Dermatol 138:132-40.
Labels: MiParea: mtDNA;mt-genetics Pathology: Aging;senescence, Myopathy
Organism: Mouse Tissue;cell: Skeletal muscle