Am J Physiol Endocrinol Metab 301: E245–E251, 2011.
First published May 10, 2011; doi:10.1152/ajpendo.00152.2011.
Review
Skeletal muscle lipid flux: running water carries no poison
Katsuhiko Funai and Clay F. Semenkovich
Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, Missouri
Submitted 25 March 2011; accepted in final form 9 May 2011
insulin resistance; lipotoxicity; lipoexpediency; peroxisome proliferator-activated
receptor
and its associated comorbidities have
been attributed mostly to chronic excess calorie consumption.
In healthy subjects, excess calories are directed to adipose
tissues where they are stored as triglycerides (TGs). However,
when some poorly defined threshold for fat storage is exceeded, as occurs in metabolic syndrome, adipose tissue becomes insulin resistant, suppression of lipolysis is diminished,
and the increased lipolysis of adipose TGs elevates circulating
free fatty acids (FFAs) (19, 90). This excess circulating fat can
be deposited in nonadipose tissues, which can result in cellular
dysfunction commonly referred to as lipotoxicity (9, 108). In
skeletal muscle, lipid-mediated signaling appears to be involved in insulin resistance (58, 80) through the effects of
several molecular species (58, 96). Skeletal muscle insulin
resistance is important in the development of type 2 diabetes
(19, 21, 86).
Figure 1 summarizes lipid metabolism in skeletal muscle.
Lipoprotein-associated lipids are broken down into FFAs by
lipoprotein lipase (LPL) on capillary endothelial cells (103).
These FFAs, along with circulating FFAs that are derived from
adipose lipolysis, are imported into skeletal muscle through
multiple pathways involving the multifunctional receptor
CD36 (16, 28), fatty acid transport proteins (FATPs), and
noncarrier mechanisms (102). Intracellular FFAs are converted
into acyl-CoAs by the membrane-associated enzyme acyl-CoA
synthases (ACSs) (24, 63) or FATPs (102). ACSs also mediate
synthesis of acyl-CoAs from FFAs that are derived from two
additional pathways: de novo lipogenesis by acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) (104) and
THE OBESITY PANDEMIC
Address for reprint requests and other correspondence: C. F. Semenkovich,
Div. of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, Campus Box 8127, 660 S. Euclid Ave., St. Louis, MO
63110 (e-mail: [email protected]).
http://www.ajpendo.org
intramuscular lipolysis by adipose triglyceride lipase (ATGL),
hormone-sensitive lipase (HSL), and monoacylglycerol lipase
(MGL) (111, 118). FAS is not as abundantly expressed in
skeletal muscle as in classically lipogenic tissues such as liver
or adipose tissues (K. Funai and C. F. Semenkovich, unpublished data); thus, it is assumed that the contribution of de novo
lipogenesis to intramuscular lipid composition is low (85).
Acyl-CoAs derived from these distinct pathways may become
compartmentalized in separate intramuscular pools. At rest,
FFAs that enter muscle cells appear initially to be directed to
the intramuscular TG pool, whereas acyl-CoAs destined for
mitochondrial ␤-oxidation appear to originate from TG lipolysis (18, 55). It is unclear whether utilization of these putative
acyl-CoA pools is interchangeable when muscle FFA oxidation
is accelerated such as during muscle contraction (22, 94, 111),
when muscles have defective intramuscular lipolysis (51), or in
the setting of diabetes, starvation, or catabolic disease. In the
absence of demand for fatty acid oxidation, acyl-CoAs undergo
a series of esterification reactions with glycerol initiated by
glycerophosphate acyltransferase (GPAT) that ultimately yield
TGs or phospholipids (17, 25, 105).
A Case for Lipoexpediency in Skeletal Muscle
Although excess fat deposition in nonadipose tissues may
induce pathology, moderate fat deposition in those same tissues is often important for maintaining normal physiology. In
skeletal muscle, lipids provide fuel for contractile activity.
During exercise, skeletal muscle endurance is highly dependent on its capacity to utilize lipids and spare muscle glycogen
(45, 95). Exercise increases circulating FFAs by promoting
adipose tissue lipolysis through several mechanisms, including
a decrease in insulin and increases in catecholamines (50, 61).
In addition to mass action driven by increased FFA availability, lipid uptake by skeletal muscle is also enhanced through
0193-1849/11 Copyright © 2011 the American Physiological Society
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Funai K, Semenkovich CF. Skeletal muscle lipid flux: running water carries no
poison. Am J Physiol Endocrinol Metab 301: E245–E251, 2011. First published
May 10, 2011; doi:10.1152/ajpendo.00152.2011.—Lipids are the most abundant
organic constituents in many humans. The rise in obesity prevalence has prompted
a need for a more refined understanding of the effects of lipid molecules on cell
physiology. In skeletal muscle, deposition of lipids can be associated with insulin
resistance that contributes to the development of diabetes. Here, we review the
evidence that muscle cells are equipped with the molecular machinery to convert
and sequester lipid molecules, thus rendering them harmless. Induction of mitochondrial and lipogenic flux in the setting of elevated lipid deposition can protect
muscle from lipid-induced “poisoning” of the cellular machinery. Lipid flux may
also be directed toward the synthesis of ligands for nuclear receptors, further
enhancing the capacity of muscle for lipid metabolism to promote favorable
physiology. Exploiting these mechanisms may have implications for the treatment
of obesity-related diseases.
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SKELETAL MUSCLE LIPID FLUX
increased cell surface translocation of CD36 (47). Exercise
also stimulates intramuscular TG lipolysis (50, 109, 111). In
trained athletes, intramuscular acyl-CoA concentrations are
elevated, and ATP synthesis may increase more than 100-fold
compared with these variables in the resting state (2). Each
exercise bout also appears to be associated with the diversion
of a portion of the acyl-CoA pool toward intramuscular TG
synthesis (49). Therefore, exercise-induced increases in skeletal muscle lipid flux are an essential component of increasing
endurance.
With endurance training, skeletal muscle metabolism shifts
so that substrate abundance and enzyme activities promote
lipid utilization and storage. Exercise training is known to
increase intramuscular TG content, an observation sometimes
described as the “athlete’s paradox” (29, 48, 78) but one that
might also be considered an “obesity paradox”. TG content
alone cannot predict muscle physiology, since elevated muscle
TG content in endurance-trained athletes is an adaptive response to increased demand for fuel utilization (45, 93),
whereas elevated muscle TG content in obese individuals is a
maladaptive response to energy excess (30, 65). In trained
muscles, exercise enhances intramuscular TG breakdown,
which promotes ATP resynthesis to spare glycogen (the depletion of which probably leads to muscle exhaustion) (8, 32).
Exercise training also induces an increase in protein abundance
for enzymes that are associated with synthesis, breakdown, and
utilization of intramuscular TG (1, 42, 52, 60, 87, 98). Thus,
skeletal muscle lipid flux caused by each bout of exercise is
further enhanced in endurance-trained athletes compared with
untrained individuals. Notably, endurance-trained muscles are
exquisitely insulin sensitive (20, 31, 40, 112).
One emerging notion is that it is not the increased content of
FFA in skeletal muscle per se but rather the accumulation of
lipid intermediates in muscle that may be deleterious. The
AJP-Endocrinol Metab • VOL
specific identities of potentially harmful lipid intermediates are
controversial, but ceramide, diacylglycerol (DAG), and certain
acyl-CoAs are implicated in skeletal muscle insulin resistance,
endoplasmic reticulum (ER) stress, mitochondrial stress, and
apoptosis (9, 58, 80, 96, 108). Since a single bout of exercise
in humans can protect against skeletal muscle insulin resistance
induced by an overnight lipid infusion (98), it is likely that in
the setting of obesity exercise activates pathways to shunt
potentially harmful lipid molecules toward mitochondrial oxidation, TG storage, or phospholipid synthesis. Thus, even with
the lipid overload that occurs in obesity, cells have the capacity
to alter proportions of different classes of lipid molecules so
that lipotoxicity is minimized. We recently coined the term
“lipoexpediency” to describe the ability of cells to modify lipid
metabolism to promote favorable physiology (72).
Data from transgenic and knockout models support the idea
that muscle can protect against lipotoxic agents by producing
neutral lipid storage. Increasing net TG synthesis by diacylglycerol acyltransferase-1 (DGAT1) overexpression (70, 106)
or ATGL inactivation (34, 59) promoted skeletal muscle insulin sensitivity. Conversely, isolated skeletal muscle from whole
body DGAT1 knockout mice exhibited insulin resistance (70).
However, insulin sensitivity alone may not reflect improved
muscle function, since DGAT1 overexpression and ATGL
knockout were accompanied by muscle abnormalities not observed in trained muscles (51, 70, 101). Mechanisms underlying the apparently beneficial increases in intramuscular TG
levels observed in trained muscles likely involve a complex set
of coordinated physiological responses. A comprehensive understanding of exercise-induced lipid flux will be required if it
will be possible to develop a strategy to mimic or enhance
exercise and its benefits.
The idea that muscle with higher oxidative demands for ATP
synthesis can protect against lipid-induced insulin resistance is
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Fig. 1. Skeletal muscle lipid flux. ACC, acetylCoA carboxylase; ACS, acyl-CoA synthase;
AGPAT, acylglycerophosphate acyltransferase; ATGL, adipose triglyceride lipase;
CD36, cluster of differentiation 36; CoA, coenzyme A; DAG, diacylglycerol; DGAT, diacylglycerol acyltransferase; DHAP, dihydroxyacetone phosphate; ER, endoplasmic reticulum;
FAS, fatty acid synthase; FFA, free fatty acids;
GDPH, glycerol-3-phosphate dehydrogenase;
glycerol-3-P, glycerol-3-phosphate; GPAT,
glycerophosphate acyltransferase; HSL, hormone-sensitive lipase; LPA, lysophosphatidic
acid; LPL, lipoprotein lipase; MAG, monoacylglycerol; MGAT, monoacylglycerol acyltransferase; MGL, monoacylglycerol lipase; PA,
phosphatidic acid; PAP, phosphatidate phosphatase (aka lipin); TG, triglycerides. Both PA
and DAG can be used for phospholipid synthesis, details of which are not depicted here.
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SKELETAL MUSCLE LIPID FLUX
also supported by data derived from transgenic mice expressing uncoupling protein-1 (UCP1) (35, 64) or UCP3 (15) in
muscle. Fuel utilization ultimately depends on ATP turnover,
so increasing mitochondrial oxidative capacity alone would not
promote lipid flux toward oxidation in the resting condition
(44, 80, 95). At rest, the mitochondrial electron transport
system operates at a small fraction of its maximal capacity.
Only in the context of increased demand for ATP resynthesis,
such as occurs with exercise, do muscles with increased mitochondrial content exhibit greater capacity for lipid oxidation.
Therefore, it is not likely that elevated mitochondrial mass
alone (73, 79) in the absence of increased energy demand can
protect muscle from lipotoxicity.
A series of novel observations over the past decade have
helped clarify some of the mechanisms by which endurance
training enhances the capacity of skeletal muscle to metabolize
lipids. Several lines of evidence suggest that peroxisome proliferator-activated receptor (PPAR)␥ coactivator-1␣ (PGC-1␣)
coordinates a broad spectrum of adaptive responses in muscle
(3, 37–39, 66, 67, 89, 117). Skeletal muscle PGC-1␣ coactivates transcription factors such as PPAR␣ and PPAR␤/␦ to
promote expression of proteins critical for lipid metabolism
(62, 81, 88). PGC-1␣-dependent transcription is induced by
multiple signaling events that are known to be activated by
exercise. These events include activation of enzymes that serve
as energy sensors, including 5=-adenosine monophosphateactivated protein kinase (AMPK) and the sirtuins, as well as
calcium sensors, including the Ca2⫹/calmodulin-dependent kinases (CaMKs) (54, 92, 114, 115). These enzymes are known
to activate the skeletal muscle transcriptional machinery involved in lipid metabolism (53, 83, 113, 116). Therefore, it
seems plausible that PGC-1␣ serves as a signaling node for
muscle adaptations occurring in response to exercise.
PPAR␣ and PPAR␤/␦ are members of a nuclear receptor
family important for regulating both metabolism and inflammation (23, 33, 74, 110). PPARs form heterodimers with
retinoid X receptors (RXRs) and bind to specific DNA sites
known as PPAR response elements (PPREs). Transcription is
activated by ligand binding to PPARs, and a wide variety of
lipid molecules have been implicated as PPAR ligands. Ligand
binding induces conformational changes resulting in dissociation of corepressors and recruitment of coactivators such as
PGC-1␣. It is likely, although not proved, that exercise-induced activation of PPARs requires the binding of a lipid
ligand to the receptor. One plausible scenario for skeletal
muscle lipid metabolism in response to exercise would thus
include the synthesis and binding of lipid ligands to PPAR␣ or
PPAR␤/␦ concurrently with the activation of PGC-1␣.
Fig. 2. A working model for PPAR ligand synthesis in
skeletal muscle. CDP, cytidine-diphosphate; CEPT1, choline/ethanolamine phosphotransferase-1; Cho, choline;
ChPT1, choline-phosphotransferase-1; DAG, diacylglycerol; Etn, ethanolamine; P, phosphate; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PEMT, phosphatidylethanolamine N-methyltransferase; PPAR, peroxisome proliferator-activated receptor.
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Roles of Specific Lipid Molecules as Ligands for PPARs
Additional clues as to how synthesis of lipid ligands may
participate in exercise-induced activation of the skeletal muscle
transcriptional machinery come from studies of altering the
lipid milieu without exercise. Raising circulating FFA in the
absence of an exercise stimulus is sufficient to increase mitochondrial biogenesis and endurance in skeletal muscle (27, 36,
75, 107), outcomes that might involve PPAR␣, PPAR␤/␦,
and/or PGC-1␣-dependent transcription (27, 36). These findings suggest that at least a portion of the exercise adaptations
that enhance the skeletal muscle’s capacity for lipid metabolism can be induced by simply replicating the increased exposure of that tissue to an appropriate lipid source. However, this
lipid intervention also caused skeletal muscle insulin resistance
(27, 36), the opposite of the insulin-sensitizing response to an
exercise intervention (10, 26, 31, 43, 91). These studies reinforce the idea that enhancing mitochondria mass alone does not
increase resting fat oxidation and that increased mitochondrial
mass alone is not sufficient to afford skeletal muscle protection
from fat-induced insulin resistance (44, 80). These studies did
not address effects of chronically increased circulating FFAs
on TG stores or lipid enzymes in muscle, so it is possible that
the processes of lipid synthesis and breakdown were unaffected
(65). Perhaps muscle contractile activity is required to promote
synthesis of specific lipid mediators that promote transcriptional programs resulting in protection of skeletal muscle from
fat-induced insulin resistance.
Because the identities of physiologically relevant ligands for
PPARs in skeletal muscle are unknown, the origin(s) of these
putative ligands is also obscure. Multiple lipogenic or lipolytic
sites might generate potential ligands. Data from several transgenic and knockout mouse models suggest that such ligands are
likely to be derived from branches of the futile cycle of lipid
synthesis and breakdown. Upregulation of DGAT1 increased
skeletal muscle expression of genes involved in mitochondrial and
fatty acid metabolism (68, 106). Conversely, inactivation of
DGAT1 decreased the expression of PPAR-dependent genes in
skeletal muscle (69). ATGL overexpression increased skeletal
muscle oxidative capacity and PPAR␤/␦ target genes (111). However, skeletal muscle from the whole body ATGL knockout
mouse does not have decreased expression of genes relevant to
fatty acid oxidation (51), an effect that may be different in cardiac
muscle (34). Skeletal muscle CD36 deficiency decreased
PPAR␤/␦ gene expression and mitochondrial fat oxidation (46,
82). In nonmuscle tissues, including liver, brain, and macrophages, the lipogenic enzyme FAS regulates PPAR␣-dependent
gene expression (12, 13, 100). FAS in adipose tissue is probably
involved in regulation of PPAR␥ activity (71, 72, 99). Lipolytic
pathways also impact PPAR activation, since ATGL (34, 84, 97)
and LPL (6, 7, 14, 119) regulate PPAR␣ at several sites.
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GPC, 18:1/18:2-GPA, and 16:0/18:2-plasmenyl-GPE but
additionally resulted in increases in isobaric 18:0/18:2-GPE
or 18:1/18:1-GPE, emphasizing the importance of diet in
modulating skeletal muscle phospholipid responses to exercise that may be relevant to PPAR signaling.
Conclusion
Exercise is the ideal treatment for chronic conditions associated
with individuals in positive energy balance, and this may be due,
in part, to its ability to partition skeletal muscle lipid molecules to
compartments where they are unlikely to “poison” muscle by
disrupting insulin signaling or energy generation. Upregulation of
intramuscular TG synthesis or lipid oxidation appears to protect
skeletal muscles from fat-induced insulin resistance. Exercise also
stimulates phospholipid biosynthesis, a process that might be
involved in the production of endogenous ligands for PPARs.
Identifying and characterizing physiologically relevant endogenous ligands for PPARs in skeletal muscle as well as the pathways
involved in their generation could lead to novel approaches for
promoting lipid flux and possibly preventing the poisoning of
muscle physiology by fats.
GRANTS
This work was supported by Grants DK-076729, DK-088083, and T32
DK-007210 from the National Institute of Diabetes and Digestive and Kidney
Diseases.
DISCLOSURES
C. F. Semenkovich is a member of the Merck Speakers Bureau.
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