Age-dependent uncoupling of mitochondria from Ca2⁺ release units in skeletal muscle.
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/100 µm2) and CRU-mitochondrial pair density (37.4 ± 0.8 vs. 27.0 ± 0.7 pairs/100 µm2) 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.
CeSI - Center for Research on Aging & DNICS, Department of Neuroscience, Imaging and Clinical Sciences, University G. d'Annunzio, Chieti, Italy.
Laura
L
Pietrangelo
CeSI - Center for Research on Aging & DNICS, Department of Neuroscience, Imaging and Clinical Sciences, University G. d'Annunzio, Chieti, Italy.
Alessandra
A
D'Incecco
Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
Alina
A
Ainbinder
CeSI - Center for Research on Aging & DNICS, Department of Neuroscience, Imaging and Clinical Sciences, University G. d'Annunzio, Chieti, Italy.
Antonio
A
Michelucci
Ludwig Boltzmann Institute of Electrical Stimulation and Physical Rehabilitation & Institute of Physical Medicine and Rehabilitation, Wilhelminenspital, Vienna, Austria.
Helmut
H
Kern
Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
Robert T
RT
Dirksen
CeSI - Center for Research on Aging & DNICS, Department of Neuroscience, Imaging and Clinical Sciences, University G. d'Annunzio, Chieti, Italy.
Simona
S
Boncompagni
CeSI - Center for Research on Aging & DNICS, Department of Neuroscience, Imaging and Clinical Sciences, University G. d'Annunzio, Chieti, Italy.
Feliciano
F
Protasi
D000367:Age Factors; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D055948:Sarcopenia / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D002118:Calcium
Ca2+ signalling; Gerotarget; excitation-contraction coupling; sarcopenia; sarcoplasmic reticulum; triad