Effects of Chronic Overload on Muscle Hypertrophy and mTOR Signaling in Young Adult and Aged Rats

Chalé-Rush, Angela; Morris, Evan P.; Kendall, Tracee L.; Brooks, Naomi; Fielding, Roger A.

doi:10.1093/gerona/glp146

Cited by 35 publications

(29 citation statements)

References 36 publications

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“…This result is similar to the lack of differences in translational signaling with overload hypertrophy despite an attenuated growth response (Chale-Rush et al, 2009). We hypothesized that muscles from aged rats would show a blunted recovery of muscle size with regrowth in pathways responsible for the balance between protein synthesis and degradation, but failed to prove this hypothesis for most pathways at the time point measured, even though there were some differences in aged muscle in general which may have influenced the regrowth response.…”

Section: Discussionsupporting

confidence: 77%

“…Muscle size lost due to starvation, glucocorticoid treatment, hind limb suspension, and limb immobilization was not recovered to the same extent in old as in young rats (Dardevet et al, 1995; Hao et al, 2011; Magne et al, 2011; Mosoni et al, 1999; Zarzhevsky et al, 2001a; Zarzhevsky et al, 2001b) and the growth response to intermittent mobility during atrophy is also inhibited (Gallegly et al, 2004). Similarly, muscle hypertrophy in response to overload is impaired in aged animals (Chale-Rush et al, 2009; Degens and Alway, 2003; Thomson and Gordon, 2006) indicating that aged muscle responds differently to a similar growth stimulus than young muscle. However, previous studies have shown contradictory results when investigating cellular mechanisms potentially responsible for the impaired growth response.…”

Section: Introductionmentioning

confidence: 99%

“…However, previous studies have shown contradictory results when investigating cellular mechanisms potentially responsible for the impaired growth response. Some reports indicate that translational signaling, particularly through the Akt-mTOR related pathway, is impaired or delayed in aged animals undergoing hypertrophy (Funai et al, 2006; Haddad and Adams, 2006; Hwee and Bodine, 2009; Thomson and Gordon, 2006), while others show no differences with young (Chale-Rush et al, 2009; Hornberger et al, 2005); also, the potential to sense mechanical activity was not changed with age (Hornberger et al, 2005). Very few studies have directly compared mechanisms in muscles from young and old to identify potential differences during regrowth after atrophy.…”

Section: Introductionmentioning

confidence: 99%

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Regrowth after skeletal muscle atrophy is impaired in aged rats, despite similar responses in signaling pathways

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Moore

et al. 2015

Experimental Gerontology

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Skeletal muscle regrowth after atrophy is impaired in the aged and in this study we hypothesized that this can be explained by a blunted response of signaling pathways and cellular processes during reloading after hind limb suspension in muscles from old rats. Male Brown Norway Fisher 344 rats at 6 (young) and 32 (old) months of age were subjected to normal ambulatory conditions (amb), hind limb suspension for 14 days (HS), and HS followed by reloading through normal ambulation for 14 days (RE); soleus muscles were used for analysis of intracellular signaling pathways and cellular processes. Soleus muscle regrowth was blunted in old compared to young rats which coincided with a recovery of serum IGF-1 and IGFBP-3 levels in young but not old. However, the response to reloading for p-Akt, p-p70s6k and p-GSK3β protein abundance was similar between muscles from young and old rats, even though main effects for age indicate an increase in activation of this protein synthesis pathway in the aged. Similarly, MAFbx mRNA levels in soleus muscle from old rats recovered to the same extent as in the young, while Murf-1 was unchanged. mRNA abundance of autophagy markers Atg5 and Atg7 showed an identical response in muscle from old compared to young rats, but beclin did not. Autophagic flux was not changed at either age at the measured time point. Apoptosis was elevated in soleus muscle from old rats particularly with HS, but recovered in HSRE and these changes were not associated with differences in caspase-3, -8 or-9 activity in any group. Protein abundance of apoptosis repressor with caspase-recruitment domain (ARC), cytosolic EndoG, as well as cytosolic and nuclear apoptosis inducing factor (AIF) were lower in muscle from old rats, and there was no age-related difference in the response to atrophy or regrowth. Soleus muscles from old rats had a higher number of ED2 positive macrophages in all groups and these decreased with HS, but recovered in HSRE in the old, while no changes were observed in the young. Pro-inflammatory cytokines in serum did not show a differential response with age to different loading conditions. Results indicate that at the measured time point the impaired skeletal muscle regrowth after atrophy in aged animals is not associated with a general lack of responsiveness to changes in loading conditions.

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Section: Discussionsupporting

confidence: 77%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Regrowth after skeletal muscle atrophy is impaired in aged rats, despite similar responses in signaling pathways

White

Confides

Moore

et al. 2015

Experimental Gerontology

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“…Thus, it is possible that the higher mTOR and S6K1 phosphorylation was associated with increased mTORC2 signaling and insulin resistance in older adults [64]. We also propose that mTOR hyperphosphorylation may contribute to anabolic resistance of aging, which is the reduced ability of aged muscle to phosphorylate mTOR and activate protein synthesis in response to anabolic stimuli such as exercise 25, 46, [65], [66], insulin 33, 38 and nutrition 67, 68 . A recent paper reported a lower mTORC1 signaling in older men as compared to younger men [67].…”

Section: Discussionmentioning

confidence: 99%

Effect of age on basal muscle protein synthesis and mTORC1 signaling in a large cohort of young and older men and women

Markofski

Dickinson

Drummond

et al. 2015

Experimental Gerontology

129

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The rate of muscle loss with aging is higher in men than women. However, women have smaller muscles throughout the adult life. Protein content is a major determinant of skeletal muscle size. This study was designed to determine if age and sex differentially impact basal muscle protein synthesis and mammalian/mechanistic Target Of Rapamycin Complex 1 (mTORC1) signaling. We performed a secondary data analysis on a cohort of 215 healthy, non-obese (BMI <30 kg·m−2) young (18–40 y; 74 men, 52 women) and older (60–87 y; 57 men, 32 women) adults. The database contained information on physical characteristics, basal muscle protein fractional synthetic rate (FSR; n=215; stable isotope methodology) and mTORC1 signaling (n=125, Western blotting). FSR and mTORC1 signaling were measured at rest and after an overnight fast. mTORC1 and S6K1 phosphorylation were higher (P<0.05) in older subjects with no sex differences. However, there were no age or sex differences or interaction for muscle FSR (p>0.05). Body mass index, fat free mass, or body fat were not significant covariates and did not influence the results. We conclude that age and sex do not influence basal muscle protein synthesis. However, basal mTORC1 hyperphosphorylation in the elderly may contribute to insulin resistance and the age-related anabolic resistance of skeletal muscle protein metabolism to nutrition and exercise.

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“…p70S6K activation, which is critical for protein synthesis, has been reported to the same [83] or increased [85] in old rats compared to adults. Using a synergist ablation model of muscle growth whereby the gastrocnemius muscle is partially ablated to cause growth in the synergist plantaris muscle, old rats had similar patterns of activation of the Akt/mTOR pathway as young rats, although the magnitude of increase in plantaris muscle mass was less for old rats than for young rats [86]. While there are conflicting results regarding changes in the Akt/mTOR pathway in studies using animal models of aging, most animal models of sarcopenia report an aging-related decline in muscle mass [80, 82, 84-86], suggesting that even if there is an increase in protein synthesis that occurs with aging it is not enough to keep up with other changes in the muscle that contribute to sarcopenia.…”

Section: Aging-related Changes In Signaling Pathways That Regulate Skmentioning

confidence: 99%

Atrogin-1, MuRF-1, and sarcopenia

2012

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Sarcopenia is one of the leading causes of disability in the elderly. Despite the growing prevalence of sarcopenia, the molecular mechanisms that control aging-related changes in muscle mass are not fully understood. The ubiquitin proteasome system is one of the major pathways that regulate muscle protein degradation, and this system plays a central role in controlling muscle size. Atrogin-1 and MuRF-1 are two E3 ubiquitin ligases that are important regulators of ubiquitin-mediated protein degradation in skeletal muscle. In this review, we will discuss: (i) aging-related changes to skeletal muscle structure and function; (ii) the regulation of protein synthesis and protein degradation by IGF-1, TGF-β, and myostatin, with emphasis on the control of atrogin-1 and MuRF-1 expression; and (iii) the potential for modulating atrogin-1 and MuRF-1 expression to treat or prevent sarcopenia.

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Effects of Chronic Overload on Muscle Hypertrophy and mTOR Signaling in Young Adult and Aged Rats

Abstract: 24% higher in Y SA and O SA compared with CON ( p = .009). Eukaryotic initiation factor 2B e phosphorylation was 33% and 9% higher in Y SA and O SA compared with CON ( p = .04). Translational signaling in young adult and aged plantaris muscle is equally responsive to chronic overload.

Cited by 35 publications

References 36 publications

Regrowth after skeletal muscle atrophy is impaired in aged rats, despite similar responses in signaling pathways

Regrowth after skeletal muscle atrophy is impaired in aged rats, despite similar responses in signaling pathways

Effect of age on basal muscle protein synthesis and mTORC1 signaling in a large cohort of young and older men and women

Atrogin-1, MuRF-1, and sarcopenia

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