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3 Myogenesis: The Development and Regeneration of Muscle

3 Myogenesis: The Development and Regeneration of Muscle

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4. CELLULAR AND MOLECULAR MECHANISMS OF PROTEIN SYNTHESIS AMONG TISSUES



FIGURE 4.5 The role of muscle regulatory factors in satellite cell response to injury and growth factors. The satellite cell may leave the

quiescent state, proliferating and differentiating into active myoblasts, capable of repairing myofiber damage and contributing to hypertrophy.

The satellite cell lineage is maintained via divergence from myoblast formation and restoration of the quiescent state (not to scale).



skeletal muscle stem cells (ie, satellite cells) continue to proliferate, relocating between the basal lamina of the

myofiber and the sarcolemma which envelops it (Schultz and McCormick, 1994). These juvenile satellite cells

eventually serve a functional role in muscle growth, as they transition to become adult, mitotically quiescent

satellite cells, the primary source of myoblasts required for muscle repair and regeneration (Relaix and

Zammit, 2012; Yin et al., 2013).

The activation of satellite cells occurs in response to several of the same exogenous and endogenous stimuli

that upregulate mTORC1 signaling. For example, satellite cells are activated in response to muscle damage,

which can occur following vigorous exercise (Fig. 4.5). Muscle injury causes satellite cells to mobilize and migrate

to the site of tissue damage (Sanes, 2003). Satellite cells can also be activated by hypertrophic stimulants and an

increase in circulating growth factors, including IGF-1, vascular endothelial growth factor (VEGF), and fibroblast

growth factor (FGF) (Ceafalan et al., 2014).

Once activated, several regulatory factors are necessary to assist satellite cells during myogenesis (Tajbakhsh,

2009). These include myogenic regulator factors (MRFs), notably the paired-box (Pax) transcription factors Pax3

and Pax7, which are expressed in adult satellite cells and have both distinct and overlapping functions in MRF

regulation (Relaix et al., 2006). Pax3 and Pax7 act to modulate myogenic progenitor cells and regulate their

differentiation, as well as the expression of downstream transcription factors, leading to a net increase in

myogenic transcription initiation and increased protein synthesis. They are also necessary for cell specificity

during development, particularly Pax3, which is required for embryonic myogenesis (Messina et al., 2009).

The exact mechanisms for how Pax3 and Pax7 regulate satellite cell biogenesis, survival, and self-renewal

remain elusive. It appears that they serve as the master regulators of myogenesis and regeneration, orchestrating

the involvement of other important MRFs to control the commitment of satellite cells to myoblast formation and

differentiation, and the fusion of myocytes to myofibers; these important MRFs include MyoD, myogenic factor

5 (Myf5), Myf6, and myogenin (Khan et al., 1999; Olguin and Pisconti, 2012; Olguin et al., 2007; Rudnicki and

Jaenisch, 1995; Seale et al., 2004).

The earliest markers of myogenic cells are Myf5 and MyoD, which are involved in the commitment

of proliferating satellite cells to myogenesis and regeneration (Rudnicki et al., 1993). These two MRFs appear to

have somewhat redundant functionality, as knocking out either of these genes still allows for myogenesis and

regeneration, albeit at limited capacity (Rudnicki et al., 1993). If both genes are silenced, however, myocyte

formation does not occur.

MyoD has been shown to regulate cell cycling and the ability of the satellite cell to move from G1 to the

S phase of mitosis (Zhang et al., 2010). Following mitotic division, satellite cell progeny undergo divergent fates

(Fig. 4.5). Decreased Pax7 expression and associated increases in MyoD expression drive differentiation, leading

to increased expression of myogenin. This cascade results in increased protein synthesis, and associated muscle

growth and repair, via terminal differentiation, whereby the myocytes are either fused with an existing myofiber

or join with other myocytes to form a new myofiber (Olguin and Pisconti, 2012). Alternatively, satellite cell



I. GENERAL AND INTRODUCTORY ASPECTS



REFERENCES



45



progeny can maintain Pax7 expression and suppress MyoD and myogenin (Zammit et al., 2004). This pathway

allows for continuance of the myogenic lineage, renewing the quiescent satellite cell pool. Maintenance of satellite

cells provides for future myogenesis in response to exercise or muscle injury.



4.4. APPLIED IMPLICATIONS OF PROTEIN SYNTHESIS IN VIVO

The highly regulated processes of protein synthesis are critical for the maintenance of human health and life.

Protein synthesis can be positively impacted by exercise, both aerobic and resistive, and nutrition, meaning

sufficient energy and amino acid intakes to meet metabolic demand. In the case of muscle protein, disuse and/or

denervation can lead to atrophy, with rates of proteolysis exceeding dramatically reduced protein synthesis.

Certain disease states—including sepsis, cancer, and uremia—are also associated with diminished protein

synthesis, upregulated proteolysis, and overall degradation of muscle protein.

Similarly, dietary energy and protein deficiencies can deprive the body of the building blocks needed to

generate new proteins. Decreased whole body protein synthesis can have serious consequences on health and

longevity. Diminished hepatic protein synthesis can lead to impaired plasma protein concentrations which may

manifest as edema and ascites. In the case of plasma transporters, movement of hydrophobic compounds

through the aqueous blood becomes diminished if transporter protein synthesis is impaired. This can severely

impact the transport of fat-soluble vitamins and plasma lipids, as well as interfere with correct dosing of

hydrophobic pharmaceuticals. Similarly, decreased antibody and immune factor production increases susceptibility to infection. Diminished enzyme and protein hormone synthesis can have system-wide implications and,

depending on the severity and duration of these limitations, can drive increased mortality. It is these deficiencies

of protein synthesis, and their associated outcomes, that illustrate the critical importance of proper regulation

and maintenance of protein synthesis.



4.5. CONCLUSIONS AND SUMMARY OF KEY POINTS

As described within this chapter:

• protein synthesis is a highly regulated process essential for life;

• polypeptides are created, based on an mRNA code, through the process of translation, requiring multiple

initiation and elongation factors working in concert with the ribosome and amino acid-charged tRNA;

• mTORC1 is the primary regulator of protein synthesis, sensitive to multiple upstream effectors and working

through various downstream factors to modulate ribosomal activity;

• satellite cells serve a key role in regulating muscle protein synthesis in order to maintain, repair, and augment

myofibers and myocytes;

• impairment of protein synthesis can result in severe physiological manifestations that may increase the risk of

morbidity and mortality.



DISCLOSURES

The opinions or assertions contained herein are the private views of the authors and are not to be construed as

official or as reflecting the views of the US Army or Department of Defense. Any citations of commercial organizations and trade names in this report do not constitute an official Department of the Army endorsement of approval

of the products or services of these organizations. The authors have no potential conflicts of interest to report.



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I. GENERAL AND INTRODUCTORY ASPECTS



C H A P T E R



5

Role of Amino Acid Transporters

in Protein Metabolism

P. M. Taylor

Division of Cell Signalling & Immunology, School of Life Sciences, University of Dundee,

Sir James Black Centre, Dundee, United Kingdom



5.1. AMINO ACID TRANSPORTERS: STRUCTURE AND MOLECULAR FUNCTION

Proteolipid cell membranes act as selective barriers to polar solutes such as amino acids (AAs) and sugars

(Stein, 1986). As AAs do not readily diffuse across lipid membranes, membrane-spanning protein “pores” are

needed to help move (or “transport”) AA between the cytosol and extracellular fluid and also between

membrane-bound compartments of cells, for example, cytosol and endosomal lumen (see Broer, 2008; Forrest

et al., 2011 for review). AA transporter proteins form such pores and act as “gatekeepers” to permit selective AA

transport across intracellular and plasma membranes. There are six major families of AA transporters in the

Solute Carrier (SLC) gene superfamily (SLC1,6,7,36,38,43 families), an “orphan” SLC16 (monocarboxylate family)

transporter, which transports aromatic AA, and three SLC families (SLC17,25,32), which include AA transporters

expressed only on intracellular membranes (see Tables 5.1 and 5.2; note that a subset of transporters localize to

both endosomal and plasma membranes). The protein products of these transporter genes are characterized by

having a primary protein structure with multiple (typically 10À12) stretches of hydrophobic AA (Fig. 5.1A).

Within the membrane, these hydrophobic regions are arranged into a series of transmembrane helices (TMH)

which typically fold themselves into two (or more) distinct opposed or intertwined domains organized around a

central “pore” translocation pathway (Fig. 5.1B). A relatively small number of underlying protein folds have been

recognized across seemingly disparate solute transporter gene families (see Forrest et al., 2011 for review).

The SLC3 gene family, although classed as AA transporters, are single TMH glycoproteins acting as regulatory

subunits for the glycoprotein-associated amino acid transporter/heteromeric amino acid transporter subfamily of

SLC7 transporters (see Table 5.1). There are also a group of 7-TMH AA transporter proteins from the LCT

(lysosomal cystine transporter) gene family expressed at the lysosomal membrane (Je´ze´gou et al., 2012; Zhai

et al., 2001) (see Table 5.2).

Transporters (or “carriers”) function essentially in similar ways to enzymes, except that they catalyze a vectorial movement of substrate across the membrane rather than a chemical reaction converting substrate to

product. Both types of catalytic mechanism are describable using principles of energetics in terms of the freeenergy of different conformational states and the energy barriers between them (see Forrest et al., 2011 for

review). A generally accepted “alternate access” model of transport involves a catalytic cycle in which sequential conformational changes “switch” the transporter protein between states in which the substrate binding site

(or “binding center”) is open to one or other side of the membrane (see Fig. 5.1C). This conformational switch

is achieved by movement of the opposing transmembrane domains of the protein, which swivel or “rock”

about the binding center (the “rocker-switch” mechanism). For most AA transporters, this does not require

a significant movement of the actual binding center, which remains located near the center of the membrane

(in cross-section). Secondary “gates” may regulate accessibility of the bound substrate to free solution



The Molecular Nutrition of Amino Acids and Proteins.

DOI: http://dx.doi.org/10.1016/B978-0-12-802167-5.00005-0



49



© 2016 Elsevier Inc. All rights reserved.



50



5. ROLE OF AMINO ACID TRANSPORTERS IN PROTEIN METABOLISM



TABLE 5.1 Amino acid transporters of plasma membranes



AA transporter family



Common acronym



Transport mechanism

designation

(see Fig. 5.1)

AA substrates



Transport

system(s)



SLC1A1-3, A6-7



EAAT1-5



S5



AAA



X2AG



SLC1A4, A5



ASCT1, 2



A2b



SNAA



ASC



SLC6A1, A11, A13



GAT1-3



S4



GABA



GABA



SLC6A5, A9



GLYT1,2



S4



Gly



Gly



SLC6A6



TauT



S4



Tau



Tau



SLC6A7



PROT



S4



Pro



Pro



SLC6A12



BGT1



S4



Betaine, GABA



Human gene

(HGNC)a



SLC1 (2.A.23)

Excitatory AA transporters



SLC6 (2.A.22)

Neurotransmitter transporters



0,1



SLC6A14



ATB



S4



NAA, CAA



B0,1



SLC6A15,

A18, A19



B0AT1-3 (XT2)



S1



NAA



B0



SLC6A17



XT1



S4



NAA



SLC6A20



IMINO (XT3)



S4



Pro, Sarcosine



Pro/β



(i) Cationic AA transporters



SLC7A1-A4



CAT1-4



U



CAA



y1



(ii) Glycoprotein-associated AA

transporters (gpaAT/HAT)c



SLC7A5, A8



LAT1,2



A1



LNAA, TH



L (L1)



SLC7 (2.A.3)



1



SLC7A6, A7



y LAT1,2



A2



NAA, CAA



y1L



SLC7A9



b0,1AT



A1



NAA, CAA,

Cystine



b0,1



SLC7A10



ascT



A1



SNAA



asc



SLC7A11



xCT



A1



Cystine, Glu



X2C



SLC7A13



AGT1



A1



AAA



SLC16A10



TAT1



U



Aromatic AA, TH T



SLC36A1-A4



PAT1-4 (LYAAT)



S2



Pro, Gly, Ala,

GABA



PAT



SLC38A1,A2,A4



SNAT1,2,4



S1



SNAA



A



SLC38A3, A5



SNAT3,5



S3



Gln, Asn, His



N



SLC43A1,A2



LAT3,4



U



LNAA



L (L2)



d



SLC16 (2.A.1)

Monocarboxylate transporters

SLC36 (2.A.18)

Proton-coupled AA transporters

SLC38 (2.A.18)

Small neutral AA transporters



SLC43 (2.A.1)

Large neutral AA transporters

a



Only AA transporters with human orthologues are included.

Na1-dependent NAA antiport, exact mechanism uncertain.

The gpaATs form heteromeric transporters with an “accessory” SLC3 (8.A.9) subunit, either SLC3A1 (rBAT/NBAT) or SLC3A2 (F42hc/CD98).

d

Primarily Na1-NAA/CAA antiport.

First column shows transporter families as classified by Human Genome Organisation (HGNC), see http://www.bioparadigms.org, and (in parentheses) by the

International Union of Biochemistry and Molecular Biology (IUBMB), see http://www.tcdb.org. See also, for example, Broer and Palacin (2011); Hediger et al.

(2013); Schioăth et al. (2013); for original sources and further details on substrate ranges and tissue expression.

AAA, anionic AA; (L/S)NAA, (large/small) neutral AA; CAA, cationic AA; TH, thyroid hormone.

b

c



I. GENERAL AND INTRODUCTORY ASPECTS



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