During exercise, muscle contraction requires a high demand for energy (adenosine triphosphate (ATP)). The increase in substrate oxidation during exercise endeavors to match ATP provision with ATP demand in a highly coordinated fashion. Carbohydrate and long-chain fatty acids (LCFA) are the primary substrates oxidized to generate the required ATP during exercise. Throughout steady-state exercise, the rate of fatty acid oxidation (FAO) exists in a reciprocal relationship with the rate of carbohydrate oxidation, and by extension, any regulatory mechanism that increases the oxidation of LCFA may increase exercise performance by sparing both muscle and liver glycogen (12). Historically, the regulation of skeletal muscle FAO has been attributed primarily to transport of lipids across the mitochondrial membranes and, specifically, by reduced malonyl-CoA (M-CoA) inhibition of carnitine palmitoyltransferase-1 (CPT-1). However, recent work has challenged this dogma, suggesting that the regulation of skeletal muscle LCFA oxidation during exercise is a more complicated process. This is now thought to extend beyond mitochondrial membrane lipid transport because several regulatory points have been suggested both internal and external to the working skeletal muscle (Fig. 1). In support of this, it has been known for decades that an increased provision of lipids to a working muscle (such as during exercise) promotes FAO; however, the mechanisms responsible for this fuel preference remain poorly defined.
During the past decade and a half, we have provided considerable evidence to support the hypothesis that the transport of lipids across the plasma and mitochondrial membranes seems to both be regulated highly, suggesting that these transport processes represent potential rate-limiting steps for skeletal muscle FAO. Specifically, using a variety of approaches, including exercise challenges (4,13), muscle denervation (21), transient transfection of cDNA (9,15,25), knockout (KO) models in mice (3,14,34), and pharmacological activation and inhibition of target proteins (5,24), we have provided evidence that fatty acid translocase (FAT)/CD36 is a key regulator of lipid transport across both the sarcolemmal and mitochondrial membranes and, therefore, rates of skeletal muscle fatty acid oxidation. This review will highlight the hypothesis that, in skeletal muscle, FAT/CD36 has an integral role in coordinating an upregulation of sarcolemmal and mitochondrial membrane transport of lipids and is, therefore, a significant control point in regulating rates of lipid oxidation during exercise. Specifically, we will discuss evidence from our research group to support the belief that FAT/CD36 functions as the primary LCFA transport protein on the sarcolemma and is intricately involved in the upregulation of sarcolemmal transport and FAO rates during exercise. In addition, we will discuss our recent work suggesting that FAT/CD36 also regulates the transport of lipids into mitochondria. In light of the evidence indicating that FAT/CD36 can upregulate both sarcolemmal fatty acid transport and increase mitochondrial FAO, FAT/CD36 may have a dual mechanism of action. By coordinating the transport of lipids across two membranes, FAT/CD36 seems to play a central role in upregulating FAO during exercise.
SARCOLEMMAL FATTY ACID TRANSPORT AND FAT/CD36
Traditionally, fatty acid transport across the sarcolemma was thought to be caused solely by passive diffusion; however, during the past decade and a half, a considerable body of literature has accumulated to highlight the importance of integral membrane proteins in facilitating the transport of lipids across the sarcolemma. The original evidence for a protein-mediated process came from experiments reporting that the rate of fatty acid transport into muscle obeyed saturation kinetics similar to those observed in well-studied protein-mediated transport systems (38). Initially, the conclusion that sarcolemmal fatty acid transport may be protein mediated was contested and it was suggested that the saturation was a reflection of the limits of intracellular metabolism rather than protein-mediated transportation events at the plasma membrane. However, subsequent studies have provided strong evidence that fatty acid uptake across the plasma membrane is indeed a saturable process and occurs independent of intracellular metabolism (5). Particularly, studies using a variety of inhibitors including proteases such as trypsin and protonase suggested that fatty acid transport was not just a passive mass action process but alternatively involved membrane proteins. Indeed, these conclusions led to the identification of a number of fatty acid transport proteins, including plasma membrane fatty acid–binding protein (FABPpm), the fatty acid translocase protein (FATP) family, and FAT/CD36 (see (11) for details on these discoveries by the various laboratories).
Independent overexpression of these various fatty acid transport proteins into mature rodent skeletal muscle has suggested that FAT/CD36, along with FATP4, possesses the highest sarcolemmal LCFA transport capacity, indicating that FAT/CD36 and FATP4 are candidate regulatory proteins that may augment FAO during exercise (25). Although less is currently known concerning the regulation of FATP4, considerable evidence indicates that FAT/CD36 is a key LCFA transporter because mechanistic studies using either a specific blocker for FAT/CD36 (sulfo-N-succinimidyl oleate (SSO)) or complete ablation of FAT/CD36 report significant inhibition of fatty acid transport at rest (3,4) and complete loss of various stimuli to acutely increase FAO (3). Despite these observations, the method by which FAT/CD36 facilitates the transport of LCFA across the sarcolemmal membrane is unknown, as putative fatty acid transport proteins do not create a pore akin to traditional transport proteins (for full review, see (32)). Therefore, based on the amino acid sequence of FAT/CD36, it has been proposed that at the sarcolemma, FAT/CD36 has a hairpin loop that projects into the interstitial space to interact with LCFA transported by albumin. FAT/CD36 then facilitates LCFA delivery and insertion into the outer leaflet of the plasma membrane. This process has been proposed to increase rates of flip-flop across the membrane and, ultimately, rates of fatty acid transport. Given this proposed mechanism, the functional effect of FAT/CD36 only occurs when FAT/CD36 is present on the plasma membrane, indicating that the expression of FAT/CD36 at the plasma membrane is paramount for an increase in the rate of fatty acid transport. Comparisons between red and white skeletal muscle highlight the finding that increased sarcolemmal FAT/CD36 increases the maximal transport (Vmax) of palmitate without altering the Km (concentration of substrate that elicits one-half Vmax). These data suggest that an increase in sarcolemmal FAT/CD36 will increase the rate at which LCFA are transported into the muscle, an effect that may be particularly advantageous during exercise (5).
FAT/CD36 AND SARCOLEMMAL FATTY ACID TRANSPORT/OXIDATION
During exercise, fatty acid transport across the sarcolemma is increased to increase FAO. FAT/CD36 within intracellular pools can be induced to translocate to the sarcolemma in rodents (≤30 min of contraction) (4) and in humans (≤2 h of moderate-intensity exercise) (6) (Fig. 2). The full time course of exercise-induced FAT/CD36 sarcolemmal translocation is currently unknown in humans and is therefore a prospect for future study.
The translocation of FAT/CD36 to the sarcolemma has been shown to substantially increase LCFA uptake and subsequent FAO whereas ablating FAT/CD36 prevents stimuli-induced increases in FAO, highlighting that the redistribution of this protein to the sarcolemma is an important mechanism to increase FAO during exercise (3). This acute redistribution of FAT/CD36 to the plasma membrane in response to exercise is hypothesized to be regulated, in part, by calcium-mediated signaling events as fatty acid transport is increased when muscle is exposed to caffeine (a cytosolic calcium level enhancer), and this increase in fatty acid transport occurs concomitantly with an increase in plasma membrane FAT/CD36 (22,39). In addition, fatty acid transport is attenuated when muscles are exposed to inhibitors for calcium signaling (CaMKII and CaMKK), and this corresponds to a prevention of FAT/CD36 translocation to the plasma membrane (1). Activation of adenosine monophosphate–activating protein kinase (AMPK) has also been implicated in the regulation of FAT/CD36 translocation to the plasma membrane (8) because AICAR, a known activator of AMPK, induces sarcolemmal FAT/CD36 translocation (3,16). However, studies in mice overexpressing a muscle-specific kinase dead form of α2 AMPK (AMPK KD) demonstrated that AMPK activity is not essential for fatty acid uptake during contractions (17), a finding supported by the observation that increased fatty acid uptake during low-intensity muscle contractions occurs in the presence of unaltered AMPK activity (29). Altogether, the role of AMPK in regulating sarcolemmal FAT/CD36 translocation during exercise remains unclear. In addition to calcium and AMPK, alternative signaling cascades have been suggested to participate in regulating FAT/CD36 translocation because inhibition of extracellular signaling receptor kinase (ERK1/2) seems to prevent contraction-induced FAT/CD36 translocation (39) and activation of protein kinase C (PKC) in cardiac myocytes induces FAT/CD36 translocation (23). Somewhat surprisingly, the role of epinephrine in regulating FAT/CD36 translocation remains to be investigated and, therefore, the hormonal arm of the exercise response should be a focus of future research.
Therefore, whereas the fundamental observation that FAT/CD36 is acutely redistributed to the sarcolemma during exercise is a well-characterized phenomenon, the molecular understanding of what regulates this process, in addition to how FAT/CD36 directly regulates lipid transport through the phospholipid bilayer, remains poorly understood.
Exercise training is a well-characterized stimulus to promote basal fat metabolism and protect against a host of metabolic pathologies associated with lipid metabolism dysregulation. In addition to the acute regulation of FAT/CD36 described above, chronic exercise training has been shown to alter both the content and subcellular location of this protein (Fig. 3). At the whole-muscle level, 9 d of moderate-intensity exercise training has been shown to increase FAT/CD36 gene expression (37). Furthermore, 2 wk of high-intensity interval training caused a significant increase in FAT/CD36 protein content, mirroring the increase in fatty acid oxidative potential of trained skeletal muscle (28). When examining the subcellular location of FAT/CD36 after a 6-wk high-intensity interval training regimen, the abundance of FAT/CD36 on the sarcolemma seems to be unaltered at rest despite an increase in whole-muscle expression (35). This pattern of adaptation to exercise training may suggest that the muscle adapts to be more flexible at the onset of exercise to rapidly increase FAO when a stimulus such as exercise is presented. Importantly, it remains to be determined if, after aerobic training, a greater FAT/CD36 translocation to the plasma membrane occurs during an acute exercise stimulus; however, this is currently being investigated.
REGULATION OF MITOCHONDRIAL FATTY ACID TRANSPORT
In addition to lipid transport across the sarcolemma, the transport of lipids into the mitochondria represents a rate-limiting step for FAO. Once inside the muscle, LCFA recruited as substrate for ATP production must enter the mitochondria. Classically, this mitochondrial membrane transport process involves 1) the activation of an LCFA to an acyl-CoA moiety by acyl-CoA synthetase (ACS); 2) the conversion of acyl-CoA to fatty acyl-carnitine via CPT-1; 3) transport of palmitoyl-carnitine across the outer and inner mitochondrial membranes; and 4) the reconversion of palmitoyl-CoA from palmitoyl-carnitine within the mitochondrial matrix via CPT-2 (18). The regulation of CPT-1 activity has been related traditionally to the interactions of M-CoA, acetyl-CoA carboxylase (ACC), and AMPK. In resting cells, CPT-1 activity can be inhibited by the presence of M-CoA. However, during exercise, metabolic signaling pathways (including AMPK) can phosphorylate and inhibit the enzyme responsible for the production of M-CoA (ACC). Therefore, exercise-induced signals are hypothesized to cause a decrease in cytosolic M-CoA levels and relieve the inhibition on CPT-1, allowing fatty acids to be transported into the mitochondria to increase FAO. However, measurements of M-CoA content in human skeletal muscle during exercise have consistently demonstrated that M-CoA content is largely unaffected by exercise and does not change despite large alterations in FAO (27,30). In addition, the primary role of AMPK in regulating M-CoA content has also been recently challenged (26,36). These conflicting data do not necessarily indicate that the AMPK/ACC/M-CoA/CPT-1 axis is unimportant but more likely highlights our lack of knowledge regarding the elegant workings of the cell. Indeed, a number of plausible explanations for these discrepancies have been suggested, including the potential role for site-specific M-CoA production in close proximity to CPT-1 (18). Altogether, it would seem that FAO during exercise possesses additional regulatory mechanisms likely working in concert with the AMPK/ACC/M-CoA/CPT-1 axis. Recent research regarding “non–M-CoA–dependent” mechanisms regulating mitochondrial FAO has been proposed, including L-carnitine content (40), M-CoA sensitivity (13), and a revisitation of previously published work regarding muscle palmitoyl-CoA concentration (20). In addition, accessory proteins to CPT-1, including putative mitochondrial fatty acid transport proteins (FAT/CD36 and FATP1 described later), may therefore play a regulatory role in mitochondrial FAO during exercise.
FAT/CD36 AND MITOCHONDRIAL FATTY ACID TRANSPORT/OXIDATION
During exercise, in addition to FAT/CD36 translocation to the sarcolemma, FAT/CD36 translocates to the mitochondria in rodents after 30 min of contraction (7) and also in human skeletal muscle after 2 h of moderate-intensity cycling exercise (but not 30 min) (13) (Fig. 2). The observation that FAT/CD36 can be acutely redistributed to the mitochondria during exercise suggests that this protein may be involved in the regulation of mitochondrial FAO during exercise. In support of this, we have shown that FAO in isolated mitochondria (14) and palmitate-supported respiration in permeabilized muscle fibers (34) is reduced approximately 20% to 35% in resting muscle from FAT/CD36 KO mice. Considering that most of the mitochondrial FAO is still present under resting conditions within FAT/CD36 KO mice, these data indicate that FAT/CD36 is not essential for mitochondrial FAO but rather plays an accessory role to CPT-1 (which is essential). The attenuation in rates of mitochondrial FAO at rest in FAT/CD36 KO mice is significantly amplified during exercise, highlighting the potential importance of this protein to the normal exercise response (14). Specifically, whereas exercise increases rates of mitochondrial FAO in wild-type mice, this response is negated in FAT/CD36 KO mice, exacerbating the difference between genotypes (14). In this respect, FAT/CD36 seems to be important in mediating exercise-induced increases in mitochondrial FAO.
Although the exact mechanism by which FAT/CD36 regulates mitochondrial FAO remains unknown, several reports support the belief that FAT/CD36 resides on the outer mitochondrial membrane and not within mitochondrial contact sites, a membrane region with concentrated CPT-1 content (10,34). Whereas we originally proposed that FAT/CD36 interacts with CPT-1, we have recently provided evidence that FAT/CD36 is located upstream of both CPT-1 and ACS on the outer mitochondrial membrane (34). This conclusion was based on the observation that palmitate-, but not palmitoyl-CoA-, supported respiration was inhibited in the FAT/CD36 KO mouse. These data are at least partially supported by others who have also not found a reduction in palmitoyl-CoA -supported respiration in FAT/CD36 KO mice (19). Therefore, we proposed a model whereby mitochondrial FAT/CD36 facilitates the delivery of LCFA to ACS, consequently increasing rates of LCFA-CoA delivery to CPT-1 and overall rates of FAO (34). Interestingly, in a muscle cell culture model overexpressing FATP1, mitochondrial ACS activity and mitochondrial FAO rates were both increased approximately 50%, highlighting the potential impact of altering ACS function with respect to mitochondrial FAO rates (33). Although speculative, these results suggest that an interaction between FATP1 and FAT/CD36 on the mitochondrial membrane would be advantageous given our proposed hypothesis that FAT/CD36 increases LCFA delivery to ACS. Effectively, this increase in fatty acid provision to ACS and subsequently to CPT-1 will increase the transport of LCFA into the mitochondria and increase rates of mitochondrial FAO. Interestingly, data from our laboratory indicates that FAT/CD36 KO mice have a 48% increase in mitochondrial FATP1 protein in resting muscle, which may represent a potential compensatory mechanism, and suggests that the reported phenotype of the FAT/CD36 KO mouse underestimates the importance of mitochondrial FAT/CD36. Whereas FATP1 may regulate rates of mitochondrial FAO, unlike FAT/CD36, FATP1 does not translocate to the mitochondria during exercise and therefore does not represent a flexible regulatory mechanism at the level of the mitochondrion. This lack of FATP1 translocation to mitochondria during exercise may also help explain the more dramatic difference between wild-type and FAT/CD36 KO mice when compared at rest versus exercise. Therefore, FAT/CD36 has emerged as a unique protein, as, to our knowledge, it represents the only protein that acutely translocates to the mitochondria to regulate rates of mitochondrial FAO. This effect seems to be particularly important during exercise when the energetic demands from LCFA oxidation are increased substantially. To date, whereas we have identified FAT/CD36 as a potential site of regulation of mitochondrial FAO, no research has been conducted on the potential signaling events responsible for trafficking FAT/CD36 to the mitochondria. However, typical exercise signaling cascades, including those derived from AMPK activation and calcium, represent attractive hypotheses as a shared mechanism of action causing simultaneous FAT/CD36 translocation to both the sarcolemma and mitochondria would likely be advantageous during exercise.
In contrast to the lack of sarcolemmal adaptation, mitochondrial FAT/CD36 content is increased with exercise training in both lean (after 6 wk of high-intensity interval training) and obese human subjects (21 wk of moderate-/high-intensity training regimen) (31,35) (Fig. 3). In addition to these human-based studies, in mature rodent muscle, overexpression of PGC-1α (a well-characterized exercise adaptation regulator) increases mitochondrial FAT/CD36 expression in concert with increasing FAO (2). Taken together, the exercise training (and PGC-1α overexpression) -induced increases in mitochondrial FAT/CD36 suggest that this protein plays a role in exercise training–induced increases in mitochondrial FAO.
DUAL MECHANISM OF ACTION
Evaluation of the Michaelis-Menten kinetics for palmitate-supported respiration in permeabilized fibers of FAT/CD36 KO mice led us to observe a very similar trend already discussed within the sarcolemmal fatty acid transport section (34). As mentioned, at the sarcolemma, Vmax for fatty acid transport is higher in red muscle than white, which coincides with higher sarcolemmal FAT/CD36, but no change in Km. Along those same lines, we found that FAT/CD36 KO mice have a lower mitochondrial palmitate respiration Vmax, but, in a similar fashion to plasma membrane transport kinetics, there was no difference in the Km for palmitate. When examining these two investigations in concert, it would seem that the presence of FAT/CD36 on the sarcolemmal and/or the mitochondrial membrane can effectively enhance and promote fatty acid transport/oxidation with an increase in fatty acid provision (Fig. 4). In other words, in a situation such as exercise when fatty acid provision is elevated, the presence of FAT/CD36 on these membranes can increase the maximal rate at which LCFA can traverse both sarcolemmal and mitochondrial membranes. Given these data on the mechanistic role of FAT/CD36 in fatty acid transport and in mitochondrial FAO, combined with the fact that exercise promotes the translocation of FAT/CD36 to the sarcolemma and the mitochondria, this protein seems to have a dual mechanism of action to increase FAO during exercise: 1) increase sarcolemmal LCFA transport and 2) increase mitochondrial LCFA transport.
Because of the reciprocal relationship between FAO and carbohydrate oxidation during steady-state exercise, an increase in FAO will effectively spare carbohydrate sources and promote exercise performance. An increase in fatty acid provision to exercising skeletal muscle has been found to be an effective strategy to increase FAO, and FAT/CD36 is currently the only identified fatty acid transport protein that translocates to both the plasma membrane and mitochondrial membrane during exercise. The ability of FAT/CD36 to both 1) increase LCFA transport at the sarcolemma and 2) increase mitochondrial fatty acid oxidation/transport has large implications regarding the provision of LCFA to mitochondria in the working skeletal muscle. This dual mechanism of action to increase FAO during exercise implicates FAT/CD36 as an important regulator of fuel selection and overall exercise performance.
This work was funded by the Natural Sciences and Engineering Research Council of Canada (G.P. Holloway and A. Bonen) and the Canadian Foundation for Innovation (G.P. Holloway and A. Bonen). B.K. Smith is supported by a Natural Sciences and Engineering Research Council of Canada graduate scholarship.
The authors declare no conflicts of interest.
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