Abstract
Aging is associated with a progressive decline in muscle mass and strength, a process known as sarcopenia. Evidence indicates that mitochondrial dysfunction plays a causal role in sarcopenia and suggests that alterations in mitochondrial dynamics/morphology may represent an underlying mechanism. Caloric restriction (CR) is among the most efficient nonpharmacological interventions to attenuate sarcopenia in rodents and is thought to exert its beneficial effects by improving mitochondrial function. However, CR effects on mitochondrial morphology and dynamics, especially in aging muscle, remain unknown. To address this issue, we investigated mitochondrial morphology and dynamics in the oxidative soleus (SOL) and glycolytic white gastrocnemius (WG) muscles of adult (9-month-old) ad libitum-fed (AL; A-AL), old (22-month-old) AL-fed (O-AL), and old CR (O-CR) rats. We show that CR attenuates the aging-related decline in the muscle-to-body-weight ratio, a sarcopenic index. CR also prevented the effects of aging on muscle fiber type composition in both muscles. With aging, the SOL displayed fragmented SubSarcolemmal (SS) and InterMyoFibrillar (IMF) mitochondria, an effect attenuated by CR. Aged WG displayed enlarged SS and more complex/branched IMF mitochondria. CR had marginal anti-aging effects on WG mitochondrial morphology. In the SOL, DRP1 (pro-fission protein) content was higher in O-AL vs YA-AL, and Mfn2 (pro-fusion) content was higher in O-CR vs A-AL. In the gastrocnemius, Mfn2, Drp1, and Fis1 (pro-fission) contents were higher in O-AL vs A-AL. CR reduced this aging-related increase in Mfn2 and Fis1 content. Overall, these results reveal for the first time that aging differentially impacts mitochondrial morphology and dynamics in different muscle fiber types, by increasing fission/fragmentation in oxidative fibers while enhancing mitochondrial size and branching in glycolytic fibers. Our results also indicate that although CR partially attenuates aging-related changes in mitochondrial dynamics in glycolytic fibers, its anti-aging effect on mitochondrial morphology is restricted to oxidative fibers.
Highlights
Skeletal muscle aging is associated with a progressive decline in muscle mass and function, a biological process known as sarcopenia (Rosenberg, 1997)
We investigated the morphology of sub-sarcolemmal (SS) and Intermyofibrillar (IMF) mitochondria in the glycolytic white gastrocnemius and the oxidative soleus muscles of adult and old rats using a 2-dimensional transmission electron microscopy approach (Picard et al, 2013a,b), in order to get a better understanding of the impact of aging and caloric restriction on mitochondrial morphology in skeletal muscles
There was no difference in muscle to body weight ratios between O-caloric restriction (CR) and A-AL rats (Figure 1C), suggesting that CR prevented the aging-related loss of relative muscle mass
Summary
Skeletal muscle aging is associated with a progressive decline in muscle mass and function, a biological process known as sarcopenia (Rosenberg, 1997). Several lines of evidence indicate that there is a sustained increase in mitochondrial dysfunction with aging in rodents and humans, which contributes to the progressive decline of muscle mass and function (Dirks and Leeuwenburgh, 2002, 2005; Drew and Leeuwenburgh, 2003; Short et al, 2005; Marzetti et al, 2008; Gouspillou et al, 2010, 2014a). Aged skeletal muscles display impaired mitochondrial bioenergetics (Drew and Leeuwenburgh, 2003; Short et al, 2005; Gouspillou et al, 2010) and an increase in mitochondrially mediated apoptosis (Dirks and Leeuwenburgh, 2002; Marzetti et al, 2008; Gouspillou et al, 2014a), which primarily contributes to the aging-related decline in muscle mass and function. This is of particular importance since it is established that mitochondrial morphology and function are interrelated, with changes in mitochondrial morphology affecting mitochondrial function (Chen et al, 2005; Jahani-Asl et al, 2007; Yu et al, 2008; Ong et al, 2010; Gomes et al, 2011) and vice versa (Benard et al, 2007)
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