Mitochondrial morphology is altered in atrophied skeletal muscle of aged mice

Abstract

Skeletal muscle aging is associated with a progressive decline in muscle mass and strength, a process termed sarcopenia. Evidence suggests that accumulation of mitochondrial dysfunction plays a causal role in sarcopenia, which could be triggered by impaired mitophagy. Mitochondrial function, mitophagy and mitochondrial morphology are interconnected aspects of mitochondrial biology, and may coordinately be altered with aging. However, mitochondrial morphology has remained challenging to characterize in muscle, and whether sarcopenia is associated with abnormal mitochondrial morphology remains unknown. Therefore, we assessed the morphology of SubSarcolemmal (SS) and InterMyoFibrillar (IMF) mitochondria in skeletal muscle of young (8-12wk-old) and old (88-96wk-old) mice using a quantitative 2-dimensional transmission electron microscopy approach. We show that sarcopenia is associated with larger and less circular SS mitochondria. Likewise, aged IMF mitochondria were longer and more branched, suggesting increased fusion and/or decreased fission. Accordingly, although no difference in the content of proteins regulating mitochondrial dynamics (Mfn1, Mfn2, Opa1 and Drp1) was observed, a mitochondrial fusion index (Mfn2-to-Drp1 ratio) was significantly increased in aged muscles. Our results reveal that sarcopenia is associated with complex changes in mitochondrial morphology that could interfere with mitochondrial function and mitophagy, and thus contribute to aging-related accumulation of mitochondrial dysfunction and sarcopenia.

Analysis of mitochondrial structure and function in the Drosophila larval musculature

“…To address the significance of mitochondrial morphology in tissue, 3-dimensional (3-D) reconstructions using either confocal microscopy or electron microscopy provide evidence that the subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondrial membranes physically interact in mouse and human skeletal muscle (Dahl et al, 2015; Picard et al, 2013). A recent paper extends these studies using quantitative 2-D transmission electron microscopy (TEM) to show that fusion indexes (Mfn2:Drp1 ratio) increase in aged muscle, possibly related to changes in mitochondrial morphology that contribute to mitochondrial dysfunction and sarcopenia (Leduc-Gaudet et al, 2015). The balance between fission and fusion seems to shift in favor of fission as myofibers differentiate.…”

Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling

“…Dysregulation of mitochondrial dynamics and aberrant mitochondrial morphology are hallmarks of aging and are thought to contribute to the pathology of numerous age-related pathologies including Alzheimer’s and Parkinson’s disease (Bonda et al, 2011; Leduc-Gaudet et al, 2015; Sebastián et al, 2016). Mitochondrial dynamics regulate several key cellular functions, including metabolic plasticity, mitochondrial turnover, and inter-organelle communication (Wai and Langer, 2016).…”

Dysfonctions mitochondriales et vieillissement musculaire

“…Alors que le, ou les, morphologie et dynamique des mitochondries étaient altérées au cours du vieillissement [54]. Chez la souris, nous avons mis en évidence que le vieillissement musculaire était associé à une augmentation de la complexité des mitochondries intermyofibrillaires 4 et à un élargissement des mitochondries sous-sarcolemmales 5 [54].…”

“…Alors que le, ou les, morphologie et dynamique des mitochondries étaient altérées au cours du vieillissement [54]. Chez la souris, nous avons mis en évidence que le vieillissement musculaire était associé à une augmentation de la complexité des mitochondries intermyofibrillaires 4 et à un élargissement des mitochondries sous-sarcolemmales 5 [54]. En lien avec ces résultats, il a également été rapporté que le ratio Mfn-2/DRP1 était augmenté chez les souris âgées, suggérant une augmentation du processus de fusion mitochondriale au cours du vieillissement musculaire [54].…”

“…Des résultats indiquant des défauts de la mitophagie lors du vieillissement musculaire ont en effet été rapportés chez l'homme [23,49]. Plus spécifiquement, ces observations suggèrent que Ainsi, les altérations de la dynamique et de la morphologie des mitochondries, rapportées par Leduc-Gaudet et al, dans les muscles âgés, pourraient représenter un mécanisme contribuant à l'accumulation de dysfonctions mitochondriales au cours du vieillissement et, ainsi, au développement de la sarcopénie [54].…”