Caloric restriction delays aging-induced cellular phenotypes in rhesus monkey skeletal muscle (original) (raw)
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Experimental Gerontology, 2012
We have previously shown that a 30% reduced calorie intake diet delayed the onset of muscle mass loss in adult monkeys between ~16 and ~22 years of age and prevented multiple cellular phenotypes of aging. In the present study we show the impact of long term (~17 years) calorie restriction (CR) on muscle aging in very old monkeys (27-33yrs) compared to age-matched Control monkeys fed ad libitum, and describe these data in the context of the whole longitudinal study. Muscle mass was preserved in very old calorie restricted (CR) monkeys compared to agematched Controls. Immunohistochemical analysis revealed an age-associated increase in the proportion of Type I fibers in the VL from Control animals that was prevented with CR. The cross sectional area (CSA) of Type II fibers was reduced in old CR animals compared to earlier time points (16-22 years of age); however, the total loss in CSA was only 15% in CR animals compared to 36% in old Controls at ~27 years of age. Atrophy was not detected in Type I fibers from either group. Notably, Type I fiber CSA was ~1.6 fold greater in VL from CR animals compared to Control animals at ~27 years of age. The frequency of VL muscle fibers with defects in mitochondrial electron transport system enzymes (ETS ab ), the absence of cytochrome c oxidase and hyper-reactive succinate dehydrogenase, were identical between Control and CR. We describe changes in ETS ab fiber CSA and determined that CR fibers respond differently to the challenge of mitochondrial deficiency. Fiber counts of intact rectus femoris muscles revealed that muscle fiber density was preserved in old CR animals. We suggest that muscle fibers from CR animals are better poised to endure and adapt to changes in muscle mass than those of Control animals.
A shift in energy metabolism anticipates the onset of sarcopenia in rhesus monkeys
Aging Cell, 2013
Age-associated skeletal muscle mass loss curtails quality of life and may contribute to defects in metabolic homeostasis in older persons. The onset of sarcopenia occurs in middle age in rhesus macaques although the trigger has yet to be identified. Here, we show that a shift in metabolism occurs in advance of the onset of sarcopenia in rhesus vastus lateralis. Multiphoton laserscanning microscopy detects a shift in the kinetics of photon emission from autofluorescent metabolic cofactors NADH and FAD. Lifetime of both fluorophores is shortened at mid-age, and this is observed in both free and bound constituent pools. Levels of FAD and free NADH are increased and the NAD/NADH redox ratio is lower. Concomitant with this, expression of fiber-type myosin isoforms is altered resulting in a shift in fiber-type distribution, activity of cytochrome c oxidase involved in mitochondrial oxidative phosphorylation is significantly lower, and the subcellular organization of mitochondria in oxidative fibers is compromised. A regulatory switch involving the transcriptional coactivator PGC-1a directs metabolic fuel utilization and governs the expression of structural proteins. Age did not significantly impact total levels of PGC-1a; however, its subcellular localization was disrupted, suggesting that PGC-1a activities may be compromised. Consistent with this, intracellular lipid storage is altered and there is shift to larger lipid droplet size that likely reflects a decline in lipid turnover or a loss in efficiency of lipid metabolism. We suggest that changes in energy metabolism contribute directly to skeletal muscle aging in rhesus monkeys.
Longitudinal analysis of early stage sarcopenia in aging rhesus monkeys
Experimental Gerontology, 2009
We present a longitudinal study using the rhesus monkey to determine biochemical and histological changes in vastus lateralis (VL) muscle fibers and whether these changes correlate with muscle mass loss. Dual energy x-ray absorptiometry (DXA) was used to determine body weight, body fat and to estimate upper leg muscle mass in twelve adult male rhesus monkeys over 12 years. Muscle mass (MM) was evaluated at years six, nine and twelve of the study. Concurrently, VL muscle biopsy samples were collected. Muscle tissue was sectioned, stained and individual muscle fibers were analyzed for fiber type, cross-sectional area (CSA) and mitochondrial electron transport system (ETS) enzyme abnormalities. The animals body weight did not change over time, however a significant increase in DXA-measured percent body fat was observed. Significant MM loss occurred in the upper leg over 12 years. A reduction in muscle fiber CSA significantly contributed to the MM loss observed in the VL of middle-aged rhesus monkeys. An age-dependent increase in muscle fibers developing mitochondrial enzyme abnormalities due to mitochondrial DNA deletion mutations was observed. The longitudinal approach of this study demonstrated that significant muscle changes occurred during middle age in a cohort of aging rhesus monkeys.
Cell Systems, 2020
Caloric restriction (CR) improves survival in nonhuman primates and delays the onset of age-related morbidities including sarcopenia, which is characterized by the age-related loss of muscle mass and function. A shift in metabolism anticipates the onset of muscle-aging phenotypes in nonhuman primates, suggesting a potential role for metabolism in the protective effects of CR. Here, we show that CR induced profound changes in muscle composition and the cellular metabolic environment. Bioinformatic analysis linked these adaptations to proteostasis, RNA processing, and lipid synthetic pathways. At the tissue level, CR maintained contractile content and attenuated age-related metabolic shifts among individual fiber types with higher mitochondrial activity, altered redox metabolism, and smaller lipid droplet size. Biometric and metabolic rate data confirm preserved metabolic efficiency in CR animals that correlated with the attenuation of age-related muscle mass and physical activity. Th...
Payne, Anthony M., Stephen L. Dodd, and Christiaan Leeuwenburgh. Life-long calorie restriction in Fischer 344 rats attenuates age-related loss in skeletal musclespecific force and reduces extracellular space. The decline in muscle function is associated with an age-related decrease in muscle mass and an age-related decline in strength. However, decreased strength is not solely due to decreased muscle mass. The age-related decline in muscle-specific force (force/muscle cross-sectional area), a measure of intrinsic muscle function, also contributes to age-related strength decline, and the mechanisms by which this occurs are only partially known. Moreover, changes in the extracellular space could have a profound effect on skeletal muscle function. Life-long calorie restriction in rodents has shown to be a powerful anti-aging intervention. In this study, we examine whether calorie restriction is able to attenuate the loss of muscle function and elevations in extracellular space associated with aging. We hypothesize that calorie restriction attenuates the age-associated decline in specific force and increases in extracellular space. Measurements of in vitro contractile properties of the extensor digitorum longus (type II) and soleus (type I) muscles from 12-mo and 26-to 28-mo-old ad libitum-fed, as well as 27-to 28-mo-old life-long calorie-restricted male Fischer 344 rats, were performed. We found that calorie restriction attenuated the age-associated decline in muscle mass-to-body mass ratio (mg/g) and strength-to-body mass ratio (N/kg) in the extensor digitorum longus muscle (P Ͻ 0.05) but not in the soleus muscle (P Ͼ 0.05). Importantly, muscle-specific force (N/cm 2 ) in the extensor digitorum longus, but not in the soleus muscle, of the old calorie-restricted rats was equal to that of the young 12-mo-old animals. Moreover, the age-associated increase in extracellular space was reduced in the fast-twitch extensor digitorum longus muscle (P Ͻ 0.05) but not in the soleus muscle with calorie restriction. We also found a significant correlation between the extracellular space and the muscle-specific force in the extensor digitorum longus (r ϭ Ϫ0.58; P Ͻ 0.05) but not in the soleus muscle (r ϭ Ϫ0.38; P Ͼ 0.05). Hence, this study shows a loss of muscle function with age and suggests that long-term calorie restriction is an effective intervention against the loss of muscle function with age. fiber specific; glycoxidative stress; aging; deletions; mitochondria; calorie restriction THE DECREASE IN MUSCLE STRENGTH with age presents a significant health problem estimated to cost society billions of dollars over the next few decades (15, 36, 37). By the year 2030, the elderly population will grow from 13 to ϳ20% of the total population, and it is estimated that $130 billion will be imposed by physical frailty . Age-related loss of strength contributes to disability and frailty in the elderly, leading to the inability to perform daily living tasks (2, 3, 5). The well-recognized age-related decrease in muscle mass contributes to the age-related decline in strength . Muscle mass declines at a greater rate with age than body mass (51) and fat-free mass (22, 55), reducing strength-to-weight ratio and possibly leading to disability and loss of independence (50, 53, 58).
Journal of Cachexia, Sarcopenia and Muscle
BackgroundMitochondrial dysfunction caused by mitochondrial (mtDNA) deletions have been associated with skeletal muscle atrophy and myofibre loss. However, whether such defects occurring in myofibres cause sarcopenia is unclear. Also, the contribution of mtDNA alterations in muscle stem cells (MuSCs) to sarcopenia remains to be investigated.MethodsWe expressed a dominant‐negative variant of the mitochondrial helicase, which induces mtDNA alterations, specifically in differentiated myofibres (K320Eskm mice) and MuSCs (K320Emsc mice), respectively, and investigated their impact on muscle structure and function by immunohistochemistry, analysis of mtDNA and respiratory chain content, muscle transcriptome and functional tests.ResultsK320Eskm mice at 24 months of age had higher levels of mtDNA deletions compared with controls in soleus (SOL, 0.07673% vs. 0.00015%, P = 0.0167), extensor digitorum longus (EDL, 0.0649 vs. 0.000925, P = 0.0015) and gastrocnemius (GAS, 0.09353 vs. 0.000425, P...
Muscle function decline and mitochondria changes in middle age precede sarcopenia in mice
Aging, 2018
Sarcopenia is the degenerative loss of muscle mass and strength with aging. Although a role of mitochondrial metabolism in muscle function and in the development of many diseases has been described, the role of mitochondrial topology and dynamics in the process of muscle aging is not fully understood. This work shows a time line of changes in both mitochondrial distribution and skeletal muscle function during mice lifespan. We isolated muscle fibers fromof mice of different ages. A fusion-like phenotype of mitochondria, together with a change in orientation perpendicular to the fiber axis was evident in the Adult group compared to Juvenile and Older groups. Moreover, an increase in the contact area between sarcoplasmic reticulum and mitochondria was evident in the same group. Together with the morphological changes, mitochondrial Caresting levels were reduced at age 10-14 months and significantly increased in the Older group. This was consistent with a reduced number of mitochondria...
The naked mole-rat (NMR) Heterocephalus glaber is an exceptionally long-lived rodent, living up to 32 years in captivity. This extended lifespan is accompanied by a phenotype of negligible senescence, a phenomenon of very slow changes in the expected physiological characteristics with age. One of the many consequences of normal aging in mammals is the devastating and progressive loss of skeletal muscle, termed sarcopenia, caused in part by respiratory enzyme dysfunction within the mitochondria of skeletal muscle fibers. Here we report that NMRs avoid sarcopenia for decades. Muscle fiber integrity and mitochondrial ultrastructure are largely maintained in aged animals. While mitochondrial Complex IV expression and activity remains stable, Complex I expression is significantly decreased. We show that aged naked mole-rat skeletal muscle tissue contains some mitochondrial DNA rearrangements, although the common mitochondrial DNA deletions associated with aging in human and other rodent skeletal muscles are not present. Interestingly, NMR skeletal muscle fibers demonstrate a significant increase in mitochondrial DNA copy number. These results have intriguing implications for the role of mitochondria in aging, suggesting Complex IV, but not Complex I, function is maintained in the long-lived naked mole rat, where sarcopenia is avoided and healthy muscle function is maintained for decades.
Muscle mass loss in Rhesus monkeys: Age of onset
Experimental Gerontology, 2005
Sarcopenia, the decline in skeletal muscle mass and function with age, contributes to increased frailty and decreased functional performance in the aging human population. The negative health consequences of muscle mass loss emphasize the need for development of a nonhuman primate model for the prevention or attenuation of sarcopenia. The age of onset for muscle mass loss in Rhesus macaques was determined using three datasets; (i) dual-energy X-ray absorptiometry (DXA) data from a cross-sectional study of 90 adult Rhesus monkeys; (ii) lean tissue mass and estimated skeletal muscle mass (ESM) from 727 DXA scans taken in 38 monkeys in a long-term, longitudinal aging study; and, (iii) quadriceps weights taken at necropsy from 13 male and 28 female Rhesus monkeys. These data indicate that both male and female Rhesus monkeys develop sarcopenia with age. The onset of sarcopenia is 14.1G2.8 years in females and 15.8G2.5 years in males. Muscle loss reaches 20% in males by 23.2 years of age and in females by 24.5 years of age. Furthermore, our data indicate percentage declines in ESM similar to those seen in humans with advancing age. These data support the suitability of the Rhesus monkey as a primate sarcopenia model.