Interactions of the super complexes: When mTORC1 meets the proteasome

Adegoke, Olasunkanmi A. J.; Beatty, Brendan; Kimball, Scot R.; Wing, Simon S.

doi:10.1016/j.biocel.2019.105638

Cited by 14 publications

(18 citation statements)

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“…healthy disease-free life span)-remains the only currently available intervention to mitigate and even reverse the age-related decline in muscle mass and function of sarcopenia. Although reduction of mTORC1 signaling is generally accepted as a fundamental mechanism implied in the pro-longevity effects of multiple strategies, including calorie restriction, intermittent fasting, and drug treatment (e.g., rapamycin), studies with rapamycin and related drugs, or genetic mTORC1 inhibition showed deleterious effects on muscle mass and functions (see Adegoke et al, 2019 and reference herein for review) (Adegoke et al, 2019). Notably, in older people mTORC1 becomes less responsive to contraction-induced activation compared with young adults (Fry et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Targeting Multiple Mitochondrial Processes by a Metabolic Modulator Prevents Sarcopenia and Cognitive Decline in SAMP8 Mice

et al. 2020

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protein was reduced in the hippocampi of PD-0E7 treated mice. In conclusion, we show that a dietary supplement tailored to boost mitochondrial respiration preserves skeletal muscle and hippocampal mitochondrial quality control and health. When administered at the early onset of age-related physical and cognitive decline, this novel metabolic inducer counteracts the deleterious effects of precocious aging in both domains.

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Section: Discussionmentioning

confidence: 99%

Targeting Multiple Mitochondrial Processes by a Metabolic Modulator Prevents Sarcopenia and Cognitive Decline in SAMP8 Mice

et al. 2020

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“…However, chondrocyte development in cell culture is sensitive to amino acid levels [121], length growth in vivo in rodent models is extremely sensitive to dietary protein intake, and given the importance of mTORC1 for bone growth [122][123][124]) and for the coordination of chondrocyte proliferation and hypertrophy [78] as shown in Figure 2, there is no reason not to believe that amino acids activate it as identified in other tissues. It is the case, however, that mTORC1 activation in relation to its interaction with the lysosome [125], may be different in chondrocytes [126]. The relationship between dietary protein intake and linear growth in infants and children is discussed below in Section 4.…”

Section: Endochondral Ossificationmentioning

confidence: 99%

“…In studies where they were both controlled independently it was demonstrated that insulin was permissive for the maximum influence of amino acids, especially leucine, [265,267,271,272] and eventually established that insulin at low physiological levels and amino acids act through independent upstream pathways to activate mTORC1 stimulation of protein synthesis. Thus, insulin signals to mTORC1 through an Akt/Rheb pathway, whereas leucine signals through the Rag pathway, interacting via the cytosolic sensors sestrins [60,125,261,273], probably sestrin1 [274] (see below for a more extensive discussion).…”

Section: Animal Studies Of Regulation Of Protein Deposition In Musclementioning

confidence: 99%

“…Recent studies of amino acid-sensing mechanisms in a variety of cell types have revealed a complex system, identifying mTORC1 activation at the lysosomal surface by leucine, arginine and S-adenosylmethionine which are sensed by cytosolic and lysosomal sensors [125,273,306] (see Figure 13). Other recent studies in both murine embryonic fibroblasts and human embryonic kidney cells have indicated that a total of 10 amino acids (alanine, arginine, asparagine, glutamine, histidine, leucine, methionine, serine, threonine, and valine) were able to promote mTORC1 activity, although the time course of mTORC1 activation by individual amino acids differed considerably.…”

Section: Amino Acids and Mpsmentioning

confidence: 99%

“…Others have reported evidence for removal of sarcomeric proteins by caspase 3 [315], or by calcium-dependent calpain proteinases [316] with subsequent proteolysis by the UPS or by autophagy [317][318][319][320][321][322]. It is the case that the UPS system has emerged as being highly regulated by phosphorylation [323] and to be controlled by mTORC1 [125,324,325] so that an insulin-mediated mechanism of control of muscle proteolysis by the UBS and autophagy working together as described by Zhao and Goldberg [326] is feasible. However, to date, attempts to identify the details of such an insulin-mediated mechanism in human muscle have not been entirely successful [303].…”

Section: Insulin and Mpbmentioning

confidence: 99%

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Interactions between Growth of Muscle and Stature: Mechanisms Involved and Their Nutritional Sensitivity to Dietary Protein: The Protein-Stat Revisited

Millward

2021

Nutrients

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Childhood growth and its sensitivity to dietary protein is reviewed within a Protein-Stat model of growth regulation. The coordination of growth of muscle and stature is a combination of genetic programming, and of two-way mechanical interactions involving the mechanotransduction of muscle growth through stretching by bone length growth, the core Protein-Stat feature, and the strengthening of bone through muscle contraction via the mechanostat. Thus, growth in bone length is the initiating event and this is always observed. Endocrine and cellular mechanisms of growth in stature are reviewed in terms of the growth hormone-insulin like growth factor-1 (GH-IGF-1) and thyroid axes and the sex hormones, which together mediate endochondral ossification in the growth plate and bone lengthening. Cellular mechanisms of muscle growth during development are then reviewed identifying (a) the difficulties posed by the need to maintain its ultrastructure during myofibre hypertrophy within the extracellular matrix and the concept of muscle as concentric “bags” allowing growth to be conceived as bag enlargement and filling, (b) the cellular and molecular mechanisms involved in the mechanotransduction of satellite and mesenchymal stromal cells, to enable both connective tissue remodelling and provision of new myonuclei to aid myofibre hypertrophy and (c) the implications of myofibre hypertrophy for protein turnover within the myonuclear domain. Experimental data from rodent and avian animal models illustrate likely changes in DNA domain size and protein turnover during developmental and stretch-induced muscle growth and between different muscle fibre types. Growth of muscle in male rats during adulthood suggests that “bag enlargement” is achieved mainly through the action of mesenchymal stromal cells. Current understanding of the nutritional regulation of protein deposition in muscle, deriving from experimental studies in animals and human adults, is reviewed, identifying regulation by amino acids, insulin and myofibre volume changes acting to increase both ribosomal capacity and efficiency of muscle protein synthesis via the mechanistic target of rapamycin complex 1 (mTORC1) and the phenomenon of a “bag-full” inhibitory signal has been identified in human skeletal muscle. The final section deals with the nutritional sensitivity of growth of muscle and stature to dietary protein in children. Growth in length/height as a function of dietary protein intake is described in the context of the breastfed child as the normative growth model, and the “Early Protein Hypothesis” linking high protein intakes in infancy to later adiposity. The extensive paediatric studies on serum IGF-1 and child growth are reviewed but their clinical relevance is of limited value for understanding growth regulation; a role in energy metabolism and homeostasis, acting with insulin to mediate adiposity, is probably more important. Information on the influence of dietary protein on muscle mass per se as opposed to lean body mass is limited but suggests that increased protein intake in children is unable to promote muscle growth in excess of that linked to genotypic growth in length/height. One possible exception is milk protein intake, which cohort and cross-cultural studies suggest can increase height and associated muscle growth, although such effects have yet to be demonstrated by randomised controlled trials.

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Understanding circadian regulation of mammalian cell function, protein homeostasis, and metabolism

Stangherlin

Seinkmane

O’Neill

2021

Current Opinion in Systems Biology

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Circadian rhythms are ∼24 h cycles of organismal and cellular activity ubiquitous to mammalian physiology. A prevailing paradigm suggests that timing information flows linearly from rhythmic transcription via protein abundance changes to drive circadian regulation of cellular function. Challenging this view, recent evidence indicates daily variation in many cellular functions arises through rhythmic post-translational regulation of protein activity. We suggest cellular circadian timing primarily functions to maintain proteome homeostasis rather than perturb it. Indeed, although relevant to timekeeping mechanism, daily rhythms of clock protein abundance may be the exception, not the rule. Informed by insights from yeast and mammalian models, we propose that optimal bioenergetic efficiency results from coupled rhythms in mammalian target of rapamycin complex activity, protein synthesis/turnover, ion transport and protein sequestration, which drive facilitatory rhythms in metabolic flux and substrate utilisation. Such daily consolidation of proteome renewal would account for many aspects of circadian cell biology whilst maintaining osmotic homeostasis.

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Interactions of the super complexes: When mTORC1 meets the proteasome

Cited by 14 publications

References 153 publications

Targeting Multiple Mitochondrial Processes by a Metabolic Modulator Prevents Sarcopenia and Cognitive Decline in SAMP8 Mice

Targeting Multiple Mitochondrial Processes by a Metabolic Modulator Prevents Sarcopenia and Cognitive Decline in SAMP8 Mice

Interactions between Growth of Muscle and Stature: Mechanisms Involved and Their Nutritional Sensitivity to Dietary Protein: The Protein-Stat Revisited

Understanding circadian regulation of mammalian cell function, protein homeostasis, and metabolism

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