Research Papers: Gerotarget (Focus on Aging):

Age-dependent uncoupling of mitochondria from Ca2+ release units in skeletal muscle

Laura Pietrangelo, Alessandra D’Incecco, Alina Ainbinder, Antonio Michelucci, Helmut Kern, Robert T. Dirksen, Simona Boncompagni and Feliciano Protasi _

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Oncotarget. 2015; 6:35358-35371. https://doi.org/10.18632/oncotarget.6139

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Laura Pietrangelo1,*, Alessandra D’Incecco1,*, Alina Ainbinder2, Antonio Michelucci1, Helmut Kern3, Robert T. Dirksen2, Simona Boncompagni1 and Feliciano Protasi1

1 CeSI - Center for Research on Aging & DNICS, Department of Neuroscience, Imaging and Clinical Sciences, University G. d’Annunzio, Chieti, Italy

2 Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA

3 Ludwig Boltzmann Institute of Electrical Stimulation and Physical Rehabilitation & Institute of Physical Medicine and Rehabilitation, Wilhelminenspital, Vienna, Austria

* These authors have contributed equally to this work

Correspondence to:

Feliciano Protasi, email:

Simona Boncompagni, email:

Keywords: Ca2+ signalling, excitation-contraction coupling, sarcopenia, sarcoplasmic reticulum, triad, Gerotarget

Received: September 10, 2015 Accepted: September 22, 2015 Published: October 16, 2015


Calcium release units (CRUs) and mitochondria control myoplasmic [Ca2+] levels and ATP production in muscle, respectively. We recently reported that these two organelles are structurally connected by tethers, which promote proximity and proper Ca2+ signaling.Here we show that disposition, ultrastructure, and density of CRUs and mitochondria and their reciprocal association are compromised in muscle from aged mice. Specifically, the density of CRUs and mitochondria is decreased in muscle fibers from aged (>24 months) vs. adult (3-12 months), with an increased percentage of mitochondria being damaged and misplaced from their normal triadic position. A significant reduction in tether (13.8±0.4 vs. 5.5±0.3 tethers/100µm2) and CRU-mitochondrial pair density (37.4±0.8 vs. 27.0±0.7 pairs/100µm2) was also observed in aged mice. In addition, myoplasmic Ca2+ transient (1.68±0.08 vs 1.37±0.03) and mitochondrial Ca2+ uptake (9.6±0.050 vs 6.58±0.54) during repetitive high frequency tetanic stimulation were significantly decreased. Finally oxidative stress, assessed from levels of 3-nitrotyrosine (3-NT), Cu/Zn superoxide-dismutase (SOD1) and Mn superoxide dismutase (SOD2) expression, were significantly increased in aged mice. The reduced association between CRUs and mitochondria with aging may contribute to impaired cross-talk between the two organelles, possibly resulting in reduced efficiency in activity-dependent ATP production and, thus, to age-dependent decline of skeletal muscle performance.

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