Skeletal Muscle Aging in F344BN F1-Hybrid Rats: I. Mitochondrial Dysfunction Contributes to the Age-Associated Reduction in VO2max

Faculty of Kinesiology, University of Calgary, 2500 University Dr. NW, Calgary, AB, Canada T2N 1N4.
The Journals of Gerontology Series A Biological Sciences and Medical Sciences (Impact Factor: 5.42). 12/2004; 59(11):1099-110. DOI: 10.1093/gerona/59.11.1099
Source: PubMed


Although mitochondrial DNA damage accumulates in aging skeletal muscles, how this relates to the decline in muscle mass-specific skeletal muscle aerobic function is unknown. We used a pump-perfused rat hind-limb model to examine maximal aerobic performance (VO(2max)) in young adult (YA; 8-9-month-old), late middle aged (LMA; 28-30-month-old) and senescent (SEN; 36-month-old) Fischer 344 x Brown Norway F1-hybrid rats at matched rates of convective O(2) delivery (QO(2)). Despite similar muscle QO(2) during a 4-minute contraction bout, muscle mass-specific VO(2max) was reduced in LMA (15%) and SEN (52%) versus YA. In plantaris muscle homogenates, nested polymerase chain reaction revealed an increased frequency of mitochondrial DNA deletions in the older animals. A greater reduction in the flux through electron transport chain complexes I-III than citrate synthase activity in the older animals suggests mitochondrial dysfunction consequent to mitochondrial DNA damage with aging. These results support the hypothesis that a reduced oxidative capacity, due in part to age-related mitochondrial dysfunction, contributes to the decline in aerobic performance in aging skeletal muscles.

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Available from: David J Baker, Jan 19, 2016
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    • "With age, the type II myofiber exhibits diminished oxidative capacity and ATP content (Proctor et al. 1995; Drew et al. 2003). Agerelated metabolic dysfunction is further evidenced by decreased mitochondrial autophagy and increased mitochondrial oxidative stress, leading to mitochondrial loss and myofiber apoptosis (Hagen et al. 2004; Chabi et al. 2008; Wohlgemuth et al. 2010). In both humans and rats, aged skeletal muscle tissue may adapt to type II myofiber loss through type I or mixed type I/II myofiber regeneration (Weber et al. 2012; Larsson et al. 1978). "
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    ABSTRACT: Mammalian skeletal muscles exhibit age-related adaptive and pathological remodeling. Several muscles in particular undergo progressive atrophy and degeneration beyond median lifespan. To better understand myocellular responses to aging, we used semi-quantitative global metabolomic profiling to characterize trends in metabolic changes between 15-month-old adult and 32-month-old aged Fischer 344 x Brown Norway (FBN) male rats. The FBN rat gastrocnemius muscle exhibits age-dependent atrophy, whereas the soleus muscle, up until 32 months, exhibits markedly fewer signs of atrophy. Both gastrocnemius and soleus muscles were analyzed, as well as plasma and urine. Compared to adult gastrocnemius, aged gastrocnemius showed evidence of reduced glycolytic metabolism, including accumulation of glycolytic, glycogenolytic, and pentose phosphate pathway intermediates. Pyruvate was elevated with age, yet levels of citrate and nicotinamide adenine dinucleotide were reduced, consistent with mitochondrial abnormalities. Indicative of muscle atrophy, 3-methylhistidine and free amino acids were elevated in aged gastrocnemius. The monounsaturated fatty acids oleate, cis-vaccenate, and palmitoleate also increased in aged gastrocnemius, suggesting altered lipid metabolism. Compared to gastrocnemius, aged soleus exhibited far fewer changes in carbohydrate metabolism, but did show reductions in several glycolytic intermediates, fumarate, malate, and flavin adenine dinucleotide. Plasma biochemicals showing the largest age-related increases included glycocholate, heme, 1,5-anhydroglucitol, 1-palmitoleoyl- glycerophosphocholine, palmitoleate, and creatine. These changes suggest reduced insulin sensitivity in aged FBN rats. Altogether, these data highlight skeletal muscle group-specific perturbations of glucose and lipid metabolism consistent with mitochondrial dysfunction in aged FBN rats.
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    • "The deleterious effects of ageing on skeletal muscle have been a topic of study since the early part of the 20th century, yielding extensive descriptions of muscular ageing in humans and laboratory animals (mice)5617, while the few such reports on domestic18 and wild animals concerned short-lived mammals19. Recently, interest in the muscular senescence of marine mammals has arisen19202122. "
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    ABSTRACT: Sarcopenia, or senile muscle atrophy, is the slow and progressive loss of muscle mass with advancing age that constitutes the most prevalent form of muscle atrophy. The effects of ageing on skeletal muscle have been extensively studied in humans and laboratory animals (mice), while the few reports on wild animals are based on short-lived mammals. The present study describes the age-related changes in cetacean muscles regarding the three factors that determine muscle mass: fibre size, fibre number, and fibre type. We show that the skeletal muscle fibres in cetaceans change with advancing age, evolving towards a slower muscle phenotype. We suggest that this physiological evolution constitutes an adaptation that allows these marine mammals to perform prolonged, deep dives.
    Full-text · Article · May 2013 · Scientific Reports
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    • "Secondly, based upon the previous suggestion that denervation may also be responsible for the extensive MHC co-expression seen in aging muscles [25], we examined the degree to which denervation co-localizes with MHC co-expression. To meet these objectives, we employed the use of a well-validated model of sarcopenia, the Fisher 344×Brown Norway F1-hybrid (F344BN) rat, and studied an age range associated with a marked degree of muscle atrophy [32], [33], [34]. The value of the F344BN rat model is that this strain has a longer lifespan and exhibits less age-related pathology than classical inbred rat strains like the Fischer 344 rat [35], [36]. "
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    ABSTRACT: Although denervation has long been implicated in aging muscle, the degree to which it is causes the fiber atrophy seen in aging muscle is unknown. To address this question, we quantified motoneuron soma counts in the lumbar spinal cord using choline acetyl transferase immunhistochemistry and quantified the size of denervated versus innervated muscle fibers in the gastrocnemius muscle using the in situ expression of the denervation-specific sodium channel, Nav₁.₅, in young adult (YA) and senescent (SEN) rats. To gain insights into the mechanisms driving myofiber atrophy, we also examined the myofiber expression of the two primary ubiquitin ligases necessary for muscle atrophy (MAFbx, MuRF1). MN soma number in lumbar spinal cord declined 27% between YA (638±34 MNs×mm⁻¹) and SEN (469±13 MNs×mm⁻¹). Nav₁.₅ positive fibers (1548±70 μm²) were 35% smaller than Nav₁.₅ negative fibers (2367±78 μm²; P<0.05) in SEN muscle, whereas Nav₁.₅ negative fibers in SEN were only 7% smaller than fibers in YA (2553±33 μm²; P<0.05) where no Nav₁.₅ labeling was seen, suggesting denervation is the primary cause of aging myofiber atrophy. Nav₁.₅ positive fibers had higher levels of MAFbx and MuRF1 (P<0.05), consistent with involvement of the proteasome proteolytic pathway in the atrophy of denervated muscle fibers in aging muscle. In summary, our study provides the first quantitative assessment of the contribution of denervation to myofiber atrophy in aging muscle, suggesting it explains the majority of the atrophy we observed. This striking result suggests a renewed focus should be placed on denervation in seeking understanding of the causes of and treatments for aging muscle atrophy.
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