Abstract
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.
Highlights
Sarcopenia, age-related decline in skeletal muscle mass and function [1,2], has a major impact on the mobility, quality of life, and health care costs of the elderly [3,4]
We previously demonstrated that Calcium release units (CRUs) and mitochondria in fast twitch skeletal muscle fibers are linked to one another by small strands, or tethers, which keeps mitochondria associated to the terminal cisternae (TC) of triads on the side opposite to transverse tubule (TT) [26]
Between 2008 and 2011, we published a series of papers investigating the functional and structural cross-talk between CRUs and mitochondria in skeletal muscle fibers [15, 17, 35,36]
Summary
Sarcopenia, age-related decline in skeletal muscle mass and function [1,2], has a major impact on the mobility, quality of life, and health care costs of the elderly [3,4]. As average life expectancy in humans is increasing, a deeper understanding of the mechanisms responsible for impaired muscle function in aging is needed to prevent disabilities, improve independence, enhance quality of life, and reduce health care costs. Skeletal muscle contraction requires Ca2+ and ATP and, depends on the proper function of the following two intracellular organelles: Ca2+ release units (CRUs) [5] and mitochondria [6]. Mitochondria are the powerhouse of the cell, as they are responsible for aerobic production of the majority of cellular ATP used to support various cellular functions in muscle (e.g. cross bridge cycling, active Ca2+ transport, etc.). Direct measurements of activity-dependent mitochondrial Ca2+ uptake using targeted Ca2+ probes have demonstrated that mitochondria sequester Ca2+ during cytoplasmic Ca2+ oscillations in many different cell types including skeletal muscle fibers [17,18, 23,24,25]
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