High mTORC1 signaling is maintained, while protein degradation pathways are perturbed in old murine skeletal muscles in the fasted state

White, Zoe; White, Rachel E.; McMahon, Christopher D.; Grounds, Miranda D.; Shavlakadze, Tea

doi:10.1016/j.biocel.2016.06.012

Cited by 48 publications

(49 citation statements)

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“…In addition to ULK1 phosphorylation, we measured protein levels of LC3 (microtubule-associated protein light chain 3) and p62, also known as sequestosome 1 (SQSTM1), as these are used as autophagy markers [45–47]. …”

Section: Resultsmentioning

confidence: 99%

“…To evaluate autophagy, ULK1 and p62 protein levels were quantified in combination with the LC3II/LC3I ratio [47, 72–75]. Insufficient autophagy can result in the accumulation of damaged and aggregated proteins, which are poorly soluble in ionic detergents (NP40 and Triton X-100) [76].…”

Section: Discussionmentioning

confidence: 99%

“…Insufficient autophagy can result in the accumulation of damaged and aggregated proteins, which are poorly soluble in ionic detergents (NP40 and Triton X-100) [76]. We have previously shown that p62 accumulates in the ionic detergent insoluble protein fraction between 4 and 15 months of age in male C57BL/6J muscle and remains elevated up until 24 months [47]. In accordance with our previous findings in male C57BL/6J mice, we observed no changes to the markers of autophagy, ULK1(Ser757), p62, or LC3II/I, between 15 and 23 months of age in either sex [47].…”

Section: Discussionmentioning

confidence: 99%

“…We have previously shown that p62 accumulates in the ionic detergent insoluble protein fraction between 4 and 15 months of age in male C57BL/6J muscle and remains elevated up until 24 months [47]. In accordance with our previous findings in male C57BL/6J mice, we observed no changes to the markers of autophagy, ULK1(Ser757), p62, or LC3II/I, between 15 and 23 months of age in either sex [47]. ULK1 is activated under low cellular nutrient states to initiate autophagosome formation [42, 77].…”

Section: Discussionmentioning

confidence: 99%

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Voluntary resistance wheel exercise from mid-life prevents sarcopenia and increases markers of mitochondrial function and autophagy in muscles of old male and female C57BL/6J mice

et al. 2016

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BackgroundThere is much interest in the capacity of resistance exercise to prevent the age-related loss of skeletal muscle mass and function, known as sarcopenia. This study investigates the molecular basis underlying the benefits of resistance exercise in aging C57BL/6J mice of both sexes.ResultsThis study is the first to demonstrate that long-term (34 weeks) voluntary resistance wheel exercise (RWE) initiated at middle age, from 15 months, prevents sarcopenia in selected hindlimb muscles and causes hypertrophy in soleus, by 23 months of age in both male and female C57BL/6J mice. Compared with 23-month-old sedentary (SED) controls, RWE (0–6 g of resistance) increased intramuscular mitochondrial density and oxidative capacity (measured by citrate synthase and NADH-TR) and increased LC3II/I ratios (a marker of autophagy) in exercised mice of both sexes. RWE also reduced mRNA expression of Gadd45α (males only) and Runx1 (females only) but had no effect on other markers of denervation including Chrng, Chrnd, Musk, and Myog. RWE increased heart mass in all mice, with a more pronounced increase in females. Significant sex differences were also noted among SED mice, with Murf1 mRNA levels increasing in male, but decreasing in old female mice between 15 and 23 months.ConclusionsOverall, long-term RWE initiated from 15 month of age significantly improved some markers of the mitochondrial and autophagosomal pathways and prevented age-related muscle wasting.Electronic supplementary materialThe online version of this article (doi:10.1186/s13395-016-0117-3) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Voluntary resistance wheel exercise from mid-life prevents sarcopenia and increases markers of mitochondrial function and autophagy in muscles of old male and female C57BL/6J mice

et al. 2016

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“…Although Tor activity was reported to increase with age in muscle, liver, lung, and stem cells (Chen et al ., 2009; Sandri et al ., 2013; Leontieva et al ., 2014; reviewed by Nacarelli et al ., 2015; Romero et al ., 2016; White et al ., 2016), other studies failed to confirm some of these findings (Baar et al ., 2016). It appears that phosphorylation of various Tor substrates is affected differentially during aging.…”

Section: Testing Predictions Of This Modelmentioning

confidence: 94%

Evidence that a mitochondrial death spiral underlies antagonistic pleiotropy

Stern

2017

Aging Cell

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SummaryThe antagonistic pleiotropy (AP) theory posits that aging occurs because alleles that are detrimental in older organisms are beneficial to growth early in life and thus are maintained in populations. Although genes of the insulin signaling pathway likely participate in AP, the insulin‐regulated cellular correlates of AP have not been identified. The mitochondrial quality control process called mitochondrial autophagy (mitophagy), which is inhibited by insulin signaling, might represent a cellular correlate of AP. In this view, rapidly growing cells are limited by ATP production; these cells thus actively inhibit mitophagy to maximize mitochondrial ATP production and compete successfully for scarce nutrients. This process maximizes early growth and reproduction, but by permitting the persistence of damaged mitochondria with mitochondrial DNA mutations, becomes detrimental in the longer term. I suggest that as mitochondrial ATP output drops, cells respond by further inhibiting mitophagy, leading to a further decrease in ATP output in a classic death spiral. I suggest that this increasing ATP deficit is communicated by progressive increases in mitochondrial ROS generation, which signals inhibition of mitophagy via ROS‐dependent activation of insulin signaling. This hypothesis clarifies a role for ROS in aging, explains why insulin signaling inhibits autophagy, and why cells become progressively more oxidized during aging with increased levels of insulin signaling and decreased levels of autophagy. I suggest that the mitochondrial death spiral is not an error in cell physiology but rather a rational approach to the problem of enabling successful growth and reproduction in a competitive world of scarce nutrients.

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Sarcopenia: Tilting the Balance of Protein Homeostasis

2019

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Sarcopenia, defined as age‐associated decline of muscle mass and function, is a risk factor for mortality and disability, and comorbid with several chronic diseases such as type II diabetes and cardiovascular diseases. Clinical trials showed that nutritional supplements had positive effects on muscle mass, but not on muscle function and strength, demonstrating our limited understanding of the molecular events involved in the ageing muscle. Protein homeostasis, the equilibrium between protein synthesis and degradation, is proposed as the major mechanism underlying the development of sarcopenia. As the key central regulator of protein homeostasis, the mammalian target of rapamycin (mTOR) is proposed to be essential for muscle hypertrophy. Paradoxically, sustained activation of mTOR complex 1 (mTORC1) is associated with a loss of sensitivity to extracellular signaling in the elderly. It is not understood why sustained mTORC1 activity, which should induce muscle hypertrophy, instead results in muscle atrophy. Here, recent findings on the implications of disrupting protein homeostasis on muscle physiology and sarcopenia development in the context of mTOR/protein kinase B (AKT) signaling are reviewed. Understanding the role of these molecular mechanisms during the ageing process will contribute towards the development of targeted therapies that will improve protein metabolism and reduce sarcopenia.

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High mTORC1 signaling is maintained, while protein degradation pathways are perturbed in old murine skeletal muscles in the fasted state

Cited by 48 publications

References 56 publications

Voluntary resistance wheel exercise from mid-life prevents sarcopenia and increases markers of mitochondrial function and autophagy in muscles of old male and female C57BL/6J mice

Voluntary resistance wheel exercise from mid-life prevents sarcopenia and increases markers of mitochondrial function and autophagy in muscles of old male and female C57BL/6J mice

Evidence that a mitochondrial death spiral underlies antagonistic pleiotropy

Sarcopenia: Tilting the Balance of Protein Homeostasis

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