Review
Amino Acid Sensing in Skeletal Muscle

https://doi.org/10.1016/j.tem.2016.06.010Get rights and content

Trends

Aging impairs endothelial cell function in skeletal muscle, thereby reducing delivery of dietary amino acids to skeletal muscle fibers.

Aging promotes anabolic resistance by impairing the ability of amino acids, insulin, or muscle contraction to increase protein synthesis in skeletal muscle.

Anabolic resistance may originate with endothelial dysfunction and impaired amino acid delivery to skeletal muscle fibers, thereby generating two distinct amino acid starvation responses [decreased mammalian/mechanistic target of rapamycin complex 1 (mTORC1) activity and increased activating transcription factor 4 (ATF4) activity], which reduce muscle protein synthesis, leading to muscle weakness and atrophy.

Potential therapeutic strategies include restoration of amino acid delivery to aged skeletal muscle via increased physical activity, dietary protein, pharmacologic vasodilators, and/or small molecules that stimulate mTORC1 and/or inhibit ATF4 in aged skeletal muscle fibers.

Aging impairs skeletal muscle protein synthesis, leading to muscle weakness and atrophy. However, the underlying molecular mechanisms remain poorly understood. Here, we review evidence that mammalian/mechanistic target of rapamycin complex 1 (mTORC1)-mediated and activating transcription factor 4 (ATF4)-mediated amino acid (AA) sensing pathways, triggered by impaired AA delivery to aged skeletal muscle, may play important roles in skeletal muscle aging. Interventions that alleviate age-related impairments in muscle protein synthesis, strength, and/or muscle mass appear to do so by reversing age-related changes in skeletal muscle AA delivery, mTORC1 activity, and/or ATF4 activity. An improved understanding of the mechanisms and roles of AA sensing pathways in skeletal muscle may lead to evidence-based strategies to attenuate sarcopenia.

Introduction

Aging reduces skeletal muscle strength and muscle quality (i.e., strength per unit muscle mass) and ultimately causes age-related skeletal muscle atrophy, also known as sarcopenia. The early stages of skeletal muscle aging are primarily marked by reduced strength, which becomes apparent around the age of 40, and can progressively impair normal activities and quality of life. The late stage of skeletal muscle aging, sarcopenia, has serious health consequences, including falls, immobility, loss of independent living, and increased mortality [1]. The cellular and molecular mechanisms of skeletal muscle aging are complex, just beginning to be revealed, and still poorly understood. Here, we review current evidence linking skeletal muscle aging to amino acid (AA) sensing mechanisms within skeletal muscle fibers.

Section snippets

Aging Impairs Delivery of Dietary AAs to Skeletal Muscle

Muscle mass is ultimately controlled by the cellular processes of protein synthesis and breakdown (i.e., protein turnover). During conditions of muscle growth or hypertrophy, the rate of protein synthesis exceeds the rate of protein breakdown (i.e., muscle protein anabolism). However, muscle catabolism occurs when the rate of protein breakdown exceeds the rate of protein synthesis. In all types of skeletal muscle atrophy, including sarcopenia, the normal balance between protein synthesis and

Mechanisms of Impaired AA Delivery to Aged Skeletal Muscle

As mentioned in the previous section, AA delivery to muscle is impaired with aging. Vascular tone in humans is determined via a balance between local vasoconstrictors and vasodilators produced by the endothelium [31]. Insulin stimulates NO production by activating endothelial NOS, which results in vasodilation, increased muscle perfusion, and capillary recruitment [25]. It is also well known that aging is associated with reduced endothelial-derived vasodilation, which appears to be due to an

Impaired AA Delivery Activates AA Sensing Mechanisms That Reduce Muscle Protein Synthesis

Because AAs are required for virtually every cellular process, impairments in skeletal muscle AA delivery could theoretically cause a catastrophic reduction in AA levels within skeletal muscle fibers. Fortunately, however, all mammalian cell types, including muscle fibers, possess evolutionarily ancient regulatory mechanisms that sense small changes in intracellular AA levels (see Figure I in Box 1). When intracellular AA levels begin to fall, these AA sensing pathways reduce protein synthesis

Physical Activity

Endothelial dysfunction is an attribute of aging. One bout of aerobic exercise can temporarily restore endothelial dysfunction, and aerobic exercise training can significantly improve endothelial function, in older adults [53]. In the aforementioned studies, acute aerobic exercise is effective at improving the anabolic action of insulin and AAs in aged human skeletal muscle [33], whereas bed rest in older adults reduces the anabolic action of AAs in muscle [38]. In addition, one study found

Concluding Remarks and Future Perspectives

The underlying mechanisms of skeletal muscle aging are still poorly understood, however, reduced AA delivery to skeletal muscle and activation of mechanisms that sense low levels of AAs within skeletal muscle appear to play important roles. Furthermore, recent advances in aging and muscle biology research emphasize the need for a better understanding of the biochemical basis of anabolic resistance, including a more complete definition of the roles and relationships of aging, physical activity,

Disclaimer Statement

C.M.A. and S.M.E. are inventors on patent applications related to ursolic acid and tomatidine, which have been filed by the University of Iowa Research Foundation and licensed to Emmyon, Inc. C.M.A. is a founder and officer of Emmyon, Inc. SME is an employee of Emmyon, Inc. C.M.A. and S.M.E. hold equity in Emmyon, Inc.

What is the biochemical basis of anabolic resistance in skeletal muscle?

What are the relative contributions of endothelial dysfunction and physical inactivity in the development

Acknowledgments

This work was supported by grants from the National Institutes of Health (R56 AG051267, P30 AG024832, R43 AG044898, R43 AR069400, and R41 AG047684), the Department of Veterans Affairs Biomedical Laboratory Research & Development Service (IBX000976A), the Department of Veterans Affairs Rehabilitation Research and Development Service (1I01RX001477), and the Fraternal Order of Eagles Diabetes Research Center at the University of Iowa.

References (67)

  • J.M. Dickinson

    Mammalian target of rapamycin complex 1 activation is required for the stimulation of human skeletal muscle protein synthesis by essential amino acids

    J. Nutr.

    (2011)
  • L. Chantranupong

    The CASTOR proteins are arginine sensor for the mTORC1 pathway

    Cell

    (2016)
  • K. Ameri

    Activating transcription factor 4

    Int. J. Biochem. Cell Biol.

    (2008)
  • S.M. Ebert

    Identification and small molecule inhibition of an activating transcription factor 4 (ATF4)-dependent pathway to age-related skeletal muscle weakness and atrophy

    J. Biol. Chem.

    (2015)
  • S.M. Ebert

    Stress-induced skeletal muscle Gadd45a expression reprograms myonuclei and causes muscle atrophy

    J. Biol. Chem.

    (2012)
  • M.M. Mamerow

    Dietary protein distribution positively influences 24-h muscle protein synthesis in healthy adults

    J. Nutr.

    (2014)
  • D.R. Morgan

    Effects of dietary omega-3 fatty acid supplementation on endothelium-dependent vasodilation in patients with chronic heart failure

    Am. J. Cardiol.

    (2006)
  • G.I. Smith

    Dietary omega-3 fatty acid supplementation increases the rate of muscle protein synthesis in older adults: a randomized controlled trial

    Am. J. Clin. Nutr.

    (2011)
  • S.D. Kunkel

    mRNA expression signatures of human skeletal muscle atrophy identify a natural compound that increases muscle mass

    Cell Metab.

    (2011)
  • M.C. Dyle

    Systems-based discovery of tomatidine as a natural small molecule inhibitor of skeletal muscle atrophy

    J. Biol. Chem.

    (2014)
  • A.J. Cruz-Jentoft

    Sarcopenia: European consensus on definition and diagnosis: report of the European working group on sarcopenia in older people

    Age Ageing

    (2010)
  • S.C. Bodine

    Skeletal muscle atrophy and the E3 ubiquitin ligases MuRF1 and MAFbx/atrogin-1

    Am. J. Physiol. Endocrinol. Metab.

    (2014)
  • S. Cohen

    Muscle wasting in disease: molecular mechanisms and promising therapies

    Nat. Rev. Drug Discov.

    (2015)
  • E. Volpi

    Basal muscle amino acid kinetics and protein synthesis in healthy young and older men

    JAMA

    (2001)
  • B.T. Wall

    Aging is accompanied by a blunted muscle protein synthetic response to protein ingestion

    PLoS One

    (2015)
  • D.R. Moore

    Protein ingestion to stimulate myofibrillar protein synthesis requires greater relative protein intakes in healthy older versus younger men

    J. Gerontol. A Biol. Sci. Med. Sci.

    (2015)
  • S.S. Bukhari

    Intake of low-dose leucine-rich essential amino acids stimulates muscle anabolism equivalently to bolus whey protein in older women at rest and after exercise

    Am. J. Physiol. Endocrinol. Metab.

    (2015)
  • M.J. Rennie

    Anabolic resistance: the effects of aging, sexual dimorphism, and immobilization on human muscle protein turnover

    Appl. Physiol. Nutr. Metab.

    (2009)
  • E. Volpi

    The response of muscle protein anabolism to combined hyperaminoacidemia and glucose-induced hyperinsulinemia is impaired in the elderly

    J. Clin. Endocrinol. Metab.

    (2000)
  • D. Cuthbertson

    Anabolic signaling deficits underlie amino acid resistance of wasting, aging muscle

    FASEB J.

    (2005)
  • D. Paddon-Jones

    Amino acid ingestion improves muscle protein synthesis in the young and elderly

    Am. J. Physiol. Endocrinol. Metab.

    (2004)
  • C.S. Katsansos

    A high proportion of leucine is required for optimal stimulation of the rate of muscle protein synthesis by essential amino acids in the elderly

    Am. J. Physiol. Endocrinol. Metab.

    (2006)
  • B.B. Rasmussen

    Insulin resistance of muscle protein metabolism in aging

    FASEB J.

    (2006)
  • Cited by (61)

    • The steroidal alkaloids α-tomatine and tomatidine: Panorama of their mode of action and pharmacological properties

      2021, Steroids
      Citation Excerpt :

      The protective effect of TD against skeletal muscle weakness and atrophy has been investigated further to show that the muscle-promoting effect of TD implicated a reduced expression of the activating transcription factor 4 (ATF4), which is one of the regulators of age-related muscle weakness and atrophy [86]. Like the pentacyclic triterpenoid ursolic acid, TD regulates ATF4-dependent gene expression to promote muscle protein synthesis [103]. An upregulation of ATF4 can be caused by different factors, such as the tumor necrosis factor-α (TNFα), one of the most important pro-inflammatory cytokines, but this effect can be suppressed by a pretreatment with TD, as shown in a study with C2C12 myoblasts.

    View all citing articles on Scopus
    View full text