RabGAPs in skeletal muscle function and exercise

in Journal of Molecular Endocrinology

Correspondence should be addressed to H Al-Hasani: hadi.al-hasani@ddz.de

The two closely related RabGAPs TBC1D1 and TBC1D4 are key signaling factors of skeletal muscle substrate utilization. In mice, deficiency in both RabGAPs leads to reduced skeletal muscle glucose transport in response to insulin and lower GLUT4 abundance. Conversely, Tbc1d1 and Tbc1d4 deficiency results in enhanced lipid use as fuel in skeletal muscle, through yet unknown mechanisms. In humans, variants in TBC1D1 and TBC1D4 are linked to obesity, insulin resistance and type 2 diabetes. While the specific function in metabolism of each of the two RabGAPs remains to be determined, TBC1D1 emerges to be controlling exercise endurance and physical capacity, whereas TBC1D4 may rather be responsible for maintaining muscle insulin sensitivity, muscle contraction, and exercise. There is growing evidence that TBC1D1 also plays an important role in skeletal muscle development, since it has been found to be associated to meat production traits in several livestock species. In addition, TBC1D1 protein abundance in skeletal muscle is regulated by both, insulin receptor and insulin-like growth factor-1 (IGF-1) receptor signaling. This review focuses on the specific roles of the two key signaling factors TBC1D1 and TBC1D4 in skeletal muscle metabolism, development and exercise physiology.

Abstract

The two closely related RabGAPs TBC1D1 and TBC1D4 are key signaling factors of skeletal muscle substrate utilization. In mice, deficiency in both RabGAPs leads to reduced skeletal muscle glucose transport in response to insulin and lower GLUT4 abundance. Conversely, Tbc1d1 and Tbc1d4 deficiency results in enhanced lipid use as fuel in skeletal muscle, through yet unknown mechanisms. In humans, variants in TBC1D1 and TBC1D4 are linked to obesity, insulin resistance and type 2 diabetes. While the specific function in metabolism of each of the two RabGAPs remains to be determined, TBC1D1 emerges to be controlling exercise endurance and physical capacity, whereas TBC1D4 may rather be responsible for maintaining muscle insulin sensitivity, muscle contraction, and exercise. There is growing evidence that TBC1D1 also plays an important role in skeletal muscle development, since it has been found to be associated to meat production traits in several livestock species. In addition, TBC1D1 protein abundance in skeletal muscle is regulated by both, insulin receptor and insulin-like growth factor-1 (IGF-1) receptor signaling. This review focuses on the specific roles of the two key signaling factors TBC1D1 and TBC1D4 in skeletal muscle metabolism, development and exercise physiology.

Skeletal muscle metabolism is crucial in controlling systemic metabolic flexibility and substrate utilization

Metabolic flexibility represents the functional ability of an organism to accordingly adapt its energy substrate preference to alterations in energy demand. In the healthy state, postprandial insulin secretion leads to enhanced glucose oxidation, while lipid oxidation is inhibited (Chomentowski et al. 2011). Conversely, the insulin-resistant state is mostly characterized by reduced use of glucose as fuel, ectopic lipid accumulation and mitochondrial dysfunction (Morino et al. 2006, Petersen & Shulman 2006).

In addition to the nutritional status such as fasting or postprandial conditions, physical activity requires a high degree of metabolic flexibility in order to ensure fuel availability and utilization in response to the increase in required energy (Egan & Zierath 2013, Hawley et al. 2014).

Exercise is widely accepted as a useful means for both the prevention and treatment of metabolic diseases (Ostman et al. 2017). The underlying mechanisms of the beneficial impact of exercise on metabolic health are not yet fully understood. However, it is clear that regular physical activity has a strong influence on whole-body energy metabolism and, more specifically, on skeletal muscle substrate utilization (Madsen et al. 2015, Maillard et al. 2016, Lao et al. 2019).

Two putative key regulators of skeletal muscle substrate utilization are the closely related Rab guanosine triphosphatase-activating proteins (RabGAPs) TBC1D1 and TBC1D4, the latter also known as AKT substrate of 160 kDa, AS160 (Dokas et al. 2013, Chadt et al. 2015). This review focuses on the specific roles of the two signaling factors TBC1D1 and TBC1D4 in skeletal muscle function, development and exercise physiology.

RabGAPs are key regulators of glucose metabolism in insulin-responsive tissues

RabGAPs control GLUT4-mediated glucose uptake into skeletal muscle and adipocytes

Glucose uptake into insulin-responsive tissues such as skeletal muscle, adipose tissue and the heart is accomplished via the facilitative glucose transporter type 4 (GLUT4) (Joost et al. 2002, Thorens & Mueckler 2010). In the basal state, that is, the absence of stimulatory elements like insulin or muscle contraction, GLUT4 is sequestered in intracellular storage vesicles (GSV) in the cytoplasm (Lauritzen 2013, Richter & Hargreaves 2013). In response to insulin, GLUT4 translocation to the plasma membrane is accelerated via a phosphorylation cascade downstream of the insulin receptor (IR) involving activation of AKT (Foley et al. 2011). Likewise, GLUT4 translocation is increased as a result of multiple stimuli/mechanisms like calcium-mediated processes, nitric oxide, reactive oxygen species and muscle contraction, the latter being associated with activation of AMP-activated kinase (AMPK) (Constable et al. 1988, Bryant et al. 2002, Tanaka et al. 2003, Horie et al. 2008, Angin et al. 2014).

The process of regulating the subcellular localization of GLUT4 is exceedingly complex and has been reviewed recently (Klip et al. 2019). A number of 21 kDa Rab GTPases have been implicated to be involved in GLUT4 vesicle traffic, and their activation state, GTP-bound or GDP-bound, is presumably regulated by the RabGAPs TBC1D1 and TBC1D4 (Zerial & McBride 2001). More than 60 different Rab proteins are described to date, exerting their main function in vesicle formation, transport, docking and fusion (Stenmark 2009, Pfeffer 2017). In adipocytes and muscular tissue, Rab8a, Rab10 and Rab14, all substrates for TBC1D1 and TBC1D4 in vitro, are associated with GLUT4 storage vesicles (Miinea et al. 2005, Roach et al. 2007, Reed et al. 2013).

While the exact function of the RabGAPs in the different steps of GLUT4 translocation is not fully understood, mutational analyses indicate that TBC1D1 and TBC1D4 exert an inhibitory effect on GLUT4 translocation that is relieved by phosphorylation at specific residues (Mafakheri et al. 2018a). Several serine (Ser) and threonine (Thr) phosphorylation sites (Tables 1, 2, 3 and 4) are described in both, TBC1D1 and TBC1D4, to be targeted by AKT and AMPK (Sano et al. 2003, Kramer et al. 2006, Roach et al. 2007, Chen et al. 2008). TBC1D1 is phosphorylated by AKT at Ser231 and Thr590 (Mafakheri et al. 2018b), whereas TBC1D4 has at least six phosphorylation motifs for AKT (Sano et al. 2003, Kramer et al. 2006).

Table 1

TBC1D1 phosphorylation sites.

SiteTarget siteTissue/cell lineReference
Insulin stimulation
 HumanThr596AKTSkeletal muscle Treebak et al. 2014
 MouseSer229AKTC2C12 myotubesPeck et al. 2009
Ser231AMPKIn vitro, cell-free extractsMafakheri et al. 2018a,b
Thr253In vitro, TA muscle lysateTaylor et al. 2008
Ser489AKTC2C12 myotubesPeck et al. 2009, Mafakheri et al. 2018a,b
Thr499AKTC2C12 myotubesPeck et al. 2009
Ser501AKTC2C12 myotubesPeck et al. 2009
Ser521C2C12 myotubesPeck et al. 2009
Thr590AKTIn vitro, cell-free extractsMafakheri et al. 2018a,b
Ser621In vitro, TA muscle lysate

C2C12 myotubes
Taylor et al. 2008, Peck et al. 2009
Ser660AMPKIn vitro, TA muscle lysate

C2C12 myotubes
Taylor et al. 2008, Peck et al. 2009
Ser697C2C12 myotubesPeck et al. 2009
Ser698C2C12 myotubesPeck et al. 2009
Ser699C2C12 myotubesPeck et al. 2009
Thr1218C2C12 myotubesPeck et al. 2009
Fasting
 HumanThr596Skeletal muscleVendelbo et al. 2012
Skeletal muscle contraction (during)
 HumanSer237AMPKSkeletal muscle cellsRamm et al. 2006, Chen et al. 2008, Frosig et al. 2010, Treebak et al. 2014
Thr489AMPKBacterially expressed Chen et al. 2008
Thr596AMPKSkeletal muscle cellsTreebak et al. 2014
Ser660AMPKSkeletal muscle cellsJessen et al. 2011, Treebak et al. 2014
Ser700AMPKSkeletal muscle cellsTreebak et al. 2014
 MouseSer237AMPKIn vitro, EDL muscleTreebak et al. 2014
Thr404AMPKIn vitro, cell-free extractsMafakheri et al. 2018a,b
Thr596AMPKIn vitro, EDL muscle Treebak et al. 2014
Ser660AMPKIn vitro, EDL muscleTreebak et al. 2014
Ser700AMPKIn vitro, EDL muscle Treebak et al. 2014
AICAR stimulation
 MouseSer145C2C12 myotubesPeck et al. 2009
Ser146C2C12 myotubesPeck et al. 2009
Ser231In vitro, TA muscle lysate Taylor et al. 2008, Chen et al. 2016
Thr253AMPKIn vitro, TA muscle lysateTaylor et al. 2008
Thr499AMPKIn vitro, TA muscle lysateTaylor et al. 2008
Ser501AKTC2C12 myotubesPeck et al. 2009
Ser521AKT+AMPKC2C12 myotubesPeck et al. 2009
Ser559AMPKC2C12 myotubesPeck et al. 2009
Ser560AKT+AMPKC2C12 myotubesPeck et al. 2009
Thr590AKTC2C12 myotubesPeck et al. 2009
Ser608AKT+AMPKC2C12 myotubesPeck et al. 2009
Ser621AKTIn vitro, TA muscle lysate

C2C12 myotubes
Taylor et al. 2008, Peck et al. 2009
Ser660AMPKIn vitro, TA muscle lysate

C2C12 myotubes
Taylor et al. 2008, Peck et al. 2009
Ser700AMPKIn vitro, TA muscle lysate

C2C12 myotubes
Taylor et al. 2008, Peck et al. 2009
 HumanSer473AKTEnhanced IGFBP-2 activation, activated AKT signaling in skeletal muscleYau et al. 2014
IGF-1 stimulation
 HumanSer473AKTEnhanced IGFBP-2 activation, activated AKT signaling in skeletal muscle Yau et al. 2014
 MouseThr172AKTIGF-1 and IGFBP-2 increase AMPK phosphorylation at Thr172 in 3T3-L1 adipocytes Assefa et al. 2017
Ser237AMPKIGFBP-2 stimulation in 3T3-L1 adipocytesAssefa et al. 2017
Ser473AKTIGF-1 and IGFBP-2 stimulate AKT Ser473 in 3T3-L1 adipocytesAssefa et al. 2017
Table 2

TBC1D4 phosphorylation sites.

SiteTarget siteTissue/cell lineReference
Insulin stimulation
 HumanSer318Skeletal muscle cellsTreebak et al. 2009, 2014
Ser341Skeletal muscle cellsTreebak et al. 2009, 2014
Ser588Skeletal muscle cellsTreebak et al. 2009
Thr642Skeletal muscle cellsTreebak et al. 2014
Ser704Skeletal muscle cellsTreebak et al. 2014
Ser751Skeletal muscle cellsTreebak et al. 2009
 MouseSer3183T3-L1 adipocytesSano et al. 2003
Ser3413T3-L1 adipocytesSano et al. 2003
Ser570AKT3T3-L1 adipocytes Sano et al. 2003
Ser5883T3-L1 adipocytesSano et al. 2003
Thr642AKT3T3-L1 adipocytes

Skeletal muscle
Sano et al. 2003, O’Neill et al. 2015
Ser711Soleus muscleTreebak et al. 2010
Thr751AKT3T3-L1 adipocytesSano et al. 2003
Insulin stimulation after contraction
 HumanSer318Skeletal muscle cellsPehmoller et al. 2009, Treebak et al. 2009, Vind et al. 2011
Ser341Skeletal muscle cellsTreebak et al. 2009, 2014
Ser588Skeletal muscle cellsTreebak et al. 2009, 2014
Ser704Skeletal muscle cellsTreebak et al. 2014
Ser751Skeletal muscle cellsTreebak et al. 2009, 2014
Thr642Skeletal muscle cellsTreebak et al. 2009, 2014
Ser666Skeletal muscle cells Treebak et al. 2014
Fasting
 HumanSer588Skeletal muscleVendelbo et al. 2012
Ser704Skeletal muscleVendelbo et al. 2012
Ser751Skeletal muscleVendelbo et al. 2012
Skeletal muscle contraction (during)
 HumanSer318AMPKSkeletal muscle Treebak et al. 2009
Ser341AMPKSkeletal muscleRamm et al. 2006, Chen et al. 2008, Frosig et al. 2010, Treebak et al. 2014
Ser588AMPKSkeletal muscleTreebak et al. 2009, 2014
Thr642AMPKSkeletal muscleTreebak et al. 2009, 2014
Ser666AMPKSkeletal muscle Treebak et al. 2009
Ser704AMPKSkeletal muscleTreebak et al. 2014
Ser751AMPKSkeletal muscleTreebak et al. 2009, 2014
 MouseThr642In vivo exercise, Gastrocnemius Kramer et al. 2006
Ser704Ex vivo contraction, EDLKramer et al. 2006
Ser711In situ contraction TA Treebak et al. 2010
 RatThr642Epitrochlearis Funai et al. 2009
Skeletal muscle contraction (post)
 HumanThr642Skeletal muscle Guerra et al. 2010
 MouseSer237AMPKIn vivo exercise, EDL muscleTreebak et al. 2014
Ser660AMPKIn vivo exercise, EDL muscleTreebak et al. 2014
Ser700AMPKIn vivo exercise, EDL muscleTreebak et al. 2014
 RatSer588In vivo exercise, Epitrochlearis Schweitzer et al. 2012, Castorena et al. 2014, Wang et al. 2018
Thr642In vivo exercise, Epitrochlearis Funai et al. 2009, 2010, Schweitzer et al. 2012, Castorena et al. 2014, Wang et al. 2018
Ser704In vivo exercise, EpitrochlearisWang et al. 2018
AICAR stimulation
 MouseSer680In vitro gastrocnemius muscle lysates Treebak et al. 2010
Ser711AMPKIn vitro gastrocnemius muscle lysates

Soleus muscle
Treebak et al. 2010
Ser761In vitro gastrocnemius muscle lysatesTreebak et al. 2010
Ser764In vitro gastrocnemius muscle lysatesTreebak et al. 2010
Ser1135In vitro gastrocnemius muscle lysatesTreebak et al. 2010
Table 3

Cross-species reference of phosphorylation sites in TBC1D1.a

HumanMouseRatStimulusReference
Ser145Ser145Ser145AICARPeck et al. 2009
Ser146Ser146Ser146AICARPeck et al. 2009
Ser235Ser229Ser229AKTChen et al. 2008, Peck et al. 2009
Ser237Ser231Ser231AMPKChen et al. 2008, Jessen et al. 2011, Treebak et al. 2014, Mafakheri et al. 2018a,b
Thr253Thr253AKTTaylor et al. 2008
Thr410Thr404Thr404AMPKMafakheri et al. 2018a,b
Ser489Ser489AKTPeck et al. 2009, Mafakheri et al. 2018a,b
Thr505Thr499Thr499AKTPeck et al. 2009
Ser527Ser521Ser521AKT/AICARPeck et al. 2009
Ser565Ser559Ser560AICARPeck et al. 2009
Ser565Ser560Ser560AICARPeck et al. 2009
Thr596Thr590Thr590AKT/Insulin/Exercise Zhou et al. 2008, Jessen et al. 2011, Treebak et al. 2014
Ser667Ser621Ser621Insulin/AICARTaylor et al. 2008
Ser667Ser660Ser662Contraction/AICAR/AMPKPeck et al. 2006, 2009, Taylor et al. 2008, Jessen et al. 2011, Treebak et al. 2014, Mafakheri et al. 2018a,b
Ser700Ser702Contraction/AICAR/AMPKTaylor et al. 2008, Treebak et al. 2014, Mafakheri et al. 2018a,b

aAccessions: TBC1D1: human (UniProt Q86TI0), mouse (Q60949 UniProt), rat (UniProt D4AC16).

Table 4

Cross-species reference of phosphorylation sites in TBC1D4.a

HumanMouseRatStimulusReference
Ser318Ser324Ser326AKT/Insulin/ExerciseSano et al. 2003, Geraghty et al. 2007, Treebak et al. 2009, 2014
Ser341Ser348Ser350AICAR/Insulin/Exercise Geraghty et al. 2007, Treebak et al. 2014
Ser570Ser577Ser579Insulin/AKTSano et al. 2003, Geraghty et al. 2007
Ser588Ser595Ser597Insulin/AKT/AICAR/ExerciseSano et al. 2003, Geraghty et al. 2007, Treebak et al. 2009, 2014
Ser591Ser598Ser600ContractionTreebak et al. 2010
Ser609Ser616Ser618ContractionTreebak et al. 2010
Thr642Thr649Thr651Insulin/AKT/AICAR/Exercise Sano et al. 2003, Geraghty et al. 2007, Treebak et al. 2009, 2014
Ser666Ser673Ser675IGF-1Geraghty et al. 2007
Ser673Ser680Ser675AICARTreebak et al. 2010
Ser704Ser711Ser713Insulin/AKT/AICAR/ExerciseTreebak et al. 2010, 2014
Thr751Thr758Ser760Insulin/AKT/AICAR/ExerciseSano et al. 2003, Geraghty et al. 2007, Treebak et al. 2009, 2014
Ser754Ser761Ser763AICARTreebak et al. 2010
Ser757Ser764Ser766AICARTreebak et al. 2010
Ser782Ser789Ser791ContractionTreebak et al. 2010
Ser1126Ser1135Ser1137AICARTreebak et al. 2010

aAccessions: TBC1D4: human (UniProt O60343), mouse (UniProt W8BYJ6), rat (RefSeq XP_017460442.1).

Upon phosphorylation, 14-3-3 proteins bind to TBC1D1 and TBC1D4 (Ramm et al. 2006, Pehmoller et al. 2009). However, there is so far no direct evidence that either phosphorylation or 14-3-3 binding affects the RabGAP activity of the proteins in vitro (Mafakheri et al. 2018b). However, insertion of a constitutive 14-3-3 binding site into a phosphorylation-deficient dominant-negative TBC1D4 mutant reversed the inhibitory effect of the mutation on GLUT4 translocation in vivo (Ramm et al. 2006, Pehmoller et al. 2009). Presumably, phosphorylation-dependent recruitment of the RabGAPs to their cognate Rab GTPases may play an important role in regulating GLUT4 trafficking.

RabGAPs are crucial regulators of whole-body glycemia

Deficiency in only one of the two RabGAP leads to only moderate impairments in insulin sensitivity and glucose tolerance in rodents, indicating a possible compensatory function of the other respective isoform (Chadt et al. 2008, Lansey et al. 2012, Dokas et al. 2013, Wang et al. 2013). In double-deficient Tbc1d1/Tbc1d4-knockout mice, insulin- as well as AICAR (5-Aminoimidazole-4-carboxamide ribonucleotide)-stimulated glucose uptake into skeletal muscle and adipose cells are almost completely abrogated and whole-body glycemia is affected to a greater extent compared to deficiency in only one of the RabGAPs (Chadt et al. 2015). Both muscle-specific Tbc1d4-knockout mice and homozygous allele carriers of a muscle-specific human loss-of-function mutation in TBC1D4 demonstrate elevated postprandial blood glucose levels, supporting the greater postulated role for this RabGAP in insulin action (Moltke et al. 2014, Xie et al. 2016). Interestingly, mutations in TBC1D1 have been linked to obesity-related traits in humans (Stone et al. 2006, Meyre et al. 2008) and mice (Chadt et al. 2008). Moreover, TBC1D1’s role in beta-cell function may also influence fasting glucose homeostasis. Glucose-stimulated insulin secretion in isolated pancreatic islets from Tbc1d1-knockout mice was greater compared to WT littermates, suggesting that TBC1D1 is a negative regulator of insulin secretion (Paglialunga et al. 2017, Stermann et al. 2018).

TBC1D1 and TBC1D4 are differentially expressed in insulin-target tissues, indicating complementary roles in signaling

Despite a high degree of homology (~47% overall amino acid identity, more than 76% in their functional GAP domain), the two RabGAPs show a differential expression pattern throughout insulin-responsive target tissues (Park et al. 2011). In mice, Tbc1d4 is mainly expressed in adipose tissues, oxidative skeletal muscle fibers (Soleus) and the heart (Wang et al. 2013). In contrast, Tbc1d1 is shown to be nearly absent in adipose tissue, but predominantly expressed in glycolytic skeletal muscle fibers (Extensor digitorum longus = EDL) (Chadt et al. 2008, An et al. 2010, Szekeres et al. 2012). In humans, however, no significant differences are described concerning TBC1D1 and TBC1D4 protein abundance in the different skeletal muscle subtypes (Jensen et al. 2012). It is postulated that TBC1D1 represents the more ancient RabGAP isoform, being present in invertebrates, while TBC1D4 evolved with the vertebrates (Chen et al. 2008). The basis of ongoing research has been the question concerning the specific role of each of the two isoforms and their respective contribution to substrate metabolism. Rodent studies indicate greater insulin-stimulated glucose uptake in oxidative Soleus muscle compared to glycolytic EDL muscle (Bonen et al. 1981, James et al. 1985). A positive correlation between the relation of oxidative skeletal muscle and whole-body insulin sensitivity has been demonstrated in humans (Oberbach et al. 2006, Stuart et al. 2013). It is likely that human oxidative skeletal muscles are more important than glycolytic fibers for maintaining glucose homeostasis in response to insulin, since insulin-stimulated glucose transport in isolated human muscle strips was associated with the relative oxidative fiber content (Zierath et al. 1996). Indeed, a decreased proportion of oxidative skeletal muscle fibers has been found in individuals with metabolic syndrome, obesity and T2D (Marin et al. 1994, Gaster et al. 2001, Stuart et al. 2013). Differences in the insulin-mediated glucose metabolism between the muscle types are likely due to fiber type-specific expression and regulation of insulin signaling. Human oxidative skeletal muscle fibers exhibit greater protein levels of IR and GLUT4 and lower protein content of AKT, TBC1D1 and TBC1D4 compared to glycolytic fibers. The phosphorylation response to insulin is not different between both fiber types. These data suggest that human oxidative skeletal muscle fiber types have a higher glucose-handling capacity but a similar sensitivity for phosphoregulation by insulin, compared to glycolytic skeletal muscle fiber types (Albers et al. 2015).

RabGAP deficiency leads to reduced GLUT4 protein abundance in insulin-target tissues

Consistent with the fiber-type-specific RabGAP expression pattern, stimulation of glucose transport is impaired mainly in glycolytic skeletal muscle of Tbc1d1-deficient mice, whereas Tbc1d4-knockout mice display defective glucose uptake after stimulation in oxidative skeletal muscle (An et al. 2010, Chadt et al. 2015). Moreover, insulin-stimulated glucose transport is also substantially reduced in adipocytes from Tbc1d4-deficient mice (Chadt et al. 2015, Zhou et al. 2017). While the expected increase in basal glucose transport due to RabGAP depletion is shown for cultured 3T3-L1 adipocytes (Roach et al. 2007), this finding is not consistently validated in intact skeletal muscles or primary adipocytes (Chadt et al. 2015). The main reason for this discrepancy is thought to be a concomitant decrease in GLUT4 protein abundance due to the RabGAP deficiency in the respective tissue type (Chadt et al. 2015, Hargett et al. 2016). The depletion of GLUT4 protein in insulin-target tissues occurs concomitantly with RabGAP deficiency in most studies. In mice reduced GLUT4 protein levels were mainly observed in glycolytic skeletal muscle types upon Tbc1d1 deficiency, whereas knockout of Tbc1d4 leads to a substantial reduction of GLUT4 abundance in oxidative skeletal muscle and the adipose tissue (Stockli et al. 2015). Moreover, human allele carriers of a nonsense p.Arg684Ter TBC1D4 variant demonstrate significantly reduced GLUT4 protein content in skeletal muscle (Moltke et al. 2014).

Of note, RabGAP deficiency-associated depletion of GLUT4 in skeletal muscle seems to occur as a result of posttranslational missorting processes since no alterations were detected on the mRNA level for Slc2a4 the gene encoding GLUT4 (Chadt et al. 2015, Stockli et al. 2015, Xie et al. 2016). The direct causal relationship between RabGAP deficiency and GLUT4 transporter reduction has been demonstrated by a study conducting a rescue experiment of GLUT4 abundance via overexpression of Tbc1d1 in skeletal muscle from Tbc1d1-knockout mice using in vivo electrotransfection (Stockli et al. 2015).

GLUT4 depletion and altered subcellular distribution contribute to impaired glucose uptake in RabGAP-deficient skeletal muscle

It has been speculated whether depletion in TBC1D1 or TBC1D4 specifically affects skeletal muscle and adipocyte glucose uptake solely by reducing GLUT4 protein abundance or whether trafficking of GLUT4-containing vesicles may be impaired as well. Cell-surface labeling of GLUT4 in skeletal muscle from Tbc1d1-deficient mice demonstrated that the amount of basal cell-surface GLUT4 in the EDL was comparable with that of WT mice despite a lower abundance of total GLUT4. In contrast, upon insulin stimulation, cell-surface GLUT4 was also reduced compared to WT mice. However, taking the reduced amount of total GLUT4 transporter into account, a higher proportion of GLUT4 was present on the cell surface in the basal state, whereas the fraction of GLUT4 present on the plasma membrane in insulin-stimulated cells was relatively normal (Chadt et al. 2015). These data suggest that RabGAP-mediated impairments in glucose transport are mainly based on the reduction in GLUT4 abundance and only secondary on defects in transporter trafficking.

Both RabGAPs interact physically with the GLUT4 vesicle-resident protein insulin-regulated aminopeptidase (IRAP) (Peck et al. 2006). In the basal state, the cytosolic domain of IRAP binds to the second PTB domain of TBC1D4 and may keep the RabGAP in proximity to the GSVs. In response to insulin, TBC1D4 dissociates from IRAP and is released into the cytoplasm (Larance et al. 2005). Likewise, TBC1D1 interacts with IRAP in a phosphorylation-dependent manner. Immunoprecipitation of IRAP resulted in co-precipitation of TBC1D1, and this interaction was abolished after phosphorylation of TBC1D1 by AMPK or AKT, indicating that IRAP recruits the RabGAPs in a phosphorylation-dependent manner to GLUT4 vesicles (Mafakheri et al. 2018b). Interestingly, in skeletal muscle from double-deficient Tbc1d1/Tbc1d4-knockout mice. IRAP and GLUT4 proteins were reduced, whereas IRAP was not changed in the single knockouts (Chadt et al. 2015). Abrogation of TBC1D1 or TBC1D4 may result in the degradation of a subset of GLUT4-containing vesicles, indicating crosstalk in RabGAP-mediated trafficking.

RabGAPs control lipid metabolism in skeletal muscle

Skeletal muscle lipid utilization is of high relevance for the maintenance of a metabolic flexible state and thus may prevent insulin resistance and ectopic lipid accumulation. Accumulation of toxic lipid intermediates such as diacylglycerols (DAGs) and ceramides in skeletal muscle are known to impair muscular insulin sensitivity by inhibiting the insulin signaling cascade, a process described as ‘lipotoxocity’ (Ragheb et al. 2009, Boucher et al. 2014, Morales et al. 2017). Both TBC1D1 and TBC1D4 have been implicated to exert an important function in skeletal muscle lipid use; therefore, these two factors can be considered as signaling hubs between glucose and lipid metabolism. The following section summarizes the specific impact of the two RabGAPs on the diverse steps of skeletal muscle lipid metabolism, such as transport of fatty acids into the cell, fatty acid oxidation (FAO) and lipid accumulation.

RabGAPs regulate FAO in skeletal muscle

Tbc1d1-, Tbc1d4- and double-deficient mice preferably use lipids as energy substrate, indicated by a lower respiratory quotient (RQ) and thus elevated fatty acid oxidation in vivo. In addition, palmitate oxidation is increased in isolated Tbc1d1-deficient skeletal muscle ex vivo (Chadt et al. 2008, 2015, Dokas et al. 2013). This phenotype is species-dependent and only present in mice, as the RQ is unaltered between Tbc1d4-deficient rats and WT littermates (Arias et al. 2019). Interestingly, isolated skeletal muscles from Tbc1d4-knockout mice demonstrated enhanced levels of FAO as well; however, whereas both glycolytic and oxidative skeletal muscles from Tbc1d1-deficient mice displayed enhanced basal FAO with no further increase by AICAR, FAO was also increased in glycolytic muscle from Tbc1d4-knockout which had normal glucose uptake, indicating independent regulation of glucose versus lipid utilization by RabGAPs (Chadt et al. 2015). Moreover, deficiency of both Tbc1d1 and Tbc1d4 did not exert additive effects on FAO as muscle from double-deficient Tbc1d1/Tbc1d4-knockout mice resembles each single knockout. These data indicate that (at least in glycolytic EDL muscle) TBC1D1 and TBC1D4 equally contribute to the effect on FAO, and the same target distal to both RabGAPs is likely to mediate the increased FAO.

A previous study demonstrated that overexpression of Tbc1d1 in mouse skeletal muscle by electrotransfection reduced the activity of β-HAD, a key enzyme in the β-oxidation pathway, resulting in impaired fatty acid oxidation (Maher et al. 2014). However, in skeletal muscle from Tbc1d1-knockout rats mitochondrial β-HAD activity was unaltered (Whitfield et al. 2017). The divergent results may be caused by compensatory mechanisms occurring during skeletal muscle development in the Tbc1d1-knockout rats as overexpression of Tbc1d1 in mouse muscle was conducted in the adult state. Interestingly, the impact of RabGAPs on lipid metabolism is not restricted to skeletal muscle. In isolated mouse pancreatic islets Tbc1d1 deficiency leads to both, enhanced insulin secretion and FAO ex vivo, presumably due to convergent RabGAP-mediated control of insulin vesicle and fatty acid transporter trafficking (Stermann et al. 2018).

To date, it is not clear whether RabGAPs have a direct regulatory connection to the oxidation of fatty acids or whether they exert their function exclusively on the level of fatty acid transport into the cell.

RabGAPs may regulate the transport of fatty acids and lipid accumulation into the skeletal muscle

Enhanced lipid use in RabGAP deficiency may result from altered trafficking and/or abundance of proteins involved in fatty acid transport and oxidation. Knockdown of Tbc1d4 in rat L6 myotubes and knockdown of Tbc1d1 in mouse C2C12 myotubes increased long-chain fatty acid uptake (Chadt et al. 2008, Miklosz et al. 2016). Similarly, both Tbc1d1- and Tbc1d4-knockout mice and Tbc1d1-knockout rats displayed increased fatty acid oxidation in isolated skeletal muscle (Chadt et al. 2015, Whitfield et al. 2017). However, while Tbc1d4-deficient L6 myotubes had increased expression levels of the fatty acid transporters fatty acid translocase (FAT/CD36) and fatty acid-binding protein (FABPpm), the abundance and plasma membrane localization of FAT/CD36 in skeletal muscle of Tbc1d1-knockout rats was not altered (Miklosz et al. 2016, Whitfield et al. 2017). Thus, assuming a species-conserved mechanism present in RabGAP deficiency, alterations in FAT/CD36 may not explain the increased lipid use in the different knockout cells. Interestingly, however, knockdown of Tbc1d4 in mouse HL-1 cardiomyocytes resulted in redistribution of FAT/CD36 to the cell surface in a Rab8-dependent manner and overexpression of a phosphorylation-deficient dominant-negative Tbc1d4 mutant had the opposite effect (Samovski et al. 2012). Further studies should investigate an involvement of other additional fatty acid transporter proteins in RabGAP signaling, including FATP-1, FATP-4 or FABPpm which may contribute to the enhanced lipid utilization across species (Nickerson et al. 2009).

Silencing of Tbc1d4 after palmitate incubation in L6 myotubes has been demonstrated to decrease lipotoxic effects by a reduction in DAG and lipid levels (Table 1) (Miklosz et al. 2017). Moreover, the intramyocellular lipid content in these cells was decreased due to an elevated FAO rate (Miklosz et al. 2017). There is a relationship between fatty acid-binding protein 3 (FABP3) content in skeletal muscle and the development of obesity and/or insulin resistance in mice. Mice with diet-induced obesity exhibit increased FABP3 content and fatty acid (FA) uptake in skeletal muscle. FABP3 may also contribute to TBC1D4 phosphorylation by insulin-dependent AKT activation in cells under palmitate-induced lipotoxic conditions (Kusudo et al. 2011). In contrast, an increase in muscle FABP3 with disturbed insulin action may result in i.m. fat deposition and could lead to insulin resistance (Kusudo et al. 2011). After a fasting period of 72 h, TBC1D4 phosphorylation of Ser588, Ser704 and Ser751 is decreased, whereas TBC1D1 phosphorylation of Thr596 is unaltered in human skeletal muscle (Vendelbo et al. 2012). This is associated with an increase in lipid content (Vendelbo et al. 2012). Interestingly, fasting did not impact phosphorylation of AMPK or AKT. Therefore it can be speculated that changes in skeletal muscle lipid content after fasting is mediated by reduced TBC1D4 signaling (Vendelbo et al. 2012).

RabGAPs are crucial factors of exercise physiology

Exercise endurance is impaired in Tbc1d1 deficiency

Contraction-stimulated GLUT4 translocation is thought to be insulin-independent, associated with AMPK activation and not reduced by insulin resistance (Marette et al. 1992, Richter & Hargreaves 2013). Tbc1d1-deficient mice showed impaired exercise performance and endurance, reduced GLUT4 protein abundance and reduced glucose uptake in skeletal muscle (Dokas et al. 2013, Chadt et al. 2015, Stockli et al. 2015). The impairment in exercise endurance could not be attributed to changes in plasma non-esterified fatty acids (NEFAs) or muscle glycogen levels, since both are unaltered in knockout animals compared to WT littermates during exercise (Stockli et al. 2015). In Tbc1d4-deficient rats, voluntary physical activity was unaltered, even though GLUT4 protein abundance was decreased and AICAR-stimulated glucose uptake into skeletal muscle was reduced (Arias et al. 2019). However, exercise performance and exercise capacity were not determined in Tbc1d4-deficient rats or Tbc1d4-knockout mice. Thus, while the data support a role of TBC1D1 in determining exercise capacity, a possible involvement of TBC1D4 remains to be clarified.

Interestingly, a recent study confirmed reduced exercise performance and impaired glucose tolerance in Tbc1d1-deficient rats, despite no changes in GLUT4 abundance thus supporting a critical role of TBC1D1 in exercise response independent of GLUT4 levels (Whitfield et al. 2017).

The different GLUT4 levels in these studies may derive from species-dependent differences between rats and mice, as TBC1D1 and TBC1D4 abundance did not differ among multiple types of rat skeletal muscles (Castorena et al. 2011, Jensen et al. 2012). However, Whitfield et al. examined GLUT4 protein abundance in white and red quadriceps muscle, whereas others could confirm a reduced GLUT4 protein content in mouse EDL muscle as well (Chen et al. 2008, Dokas et al. 2013, Stockli et al. 2015). Further studies are required to establish the relation of GLUT4 and TBC1D1 in different muscle types and species.

Exercise potentiates insulin-stimulated RabGAP phosphorylation

Human TBC1D1 is phosphorylated in response to contraction by AMPK at Ser237, Thr489, Thr596, Ser660 and Ser700 in vitro (Fig. 1 and Table 2) (Ramm et al. 2006, Chen et al. 2008, Frosig et al. 2010, Treebak et al. 2014). Recently, Thr404 (corresponding to Thr410 in humans) could be detected as a novel AMPK-dependent phosphorylation site (Table 4) (Mafakheri et al. 2018b). In humans, AMPK has been shown to phosphorylate TBC1D4 at Ser341, Ser588 and Ser751, in vitro (Fig. 1 and Tables 3, 5) (Ramm et al. 2006, Chen et al. 2008, Treebak et al. 2014).

Table 5

Summary of RabGAP action in lipid metabolism.

TBC1D1-KO/KdTBC1D4-KO/KdReference
Respiratory quotient (RQ) or Respiratory Exchange Ratio (RER)↓ in mice

↓ ↔ RER in rats
↓ in miceChadt et al. 2008, 2015, Dokas et al. 2013, Whitfield et al. 2017, Arias et al. 2019

FAO in skeletal muscle
↑ basal (EDL mouse muscle)↑ basal (EDL mouse muscle)Chadt et al. 2008, 2015, Dokas et al. 2013
↑ basal (Soleus mouse muscle)↔ basal (Soleus mouse muscle)Chadt et al. 2008, 2015, Dokas et al. 2013
↔ AICAR (EDL + Soleus mouse muscles)↔ AICAR (EDL + Soleus mouse muscles)Chadt et al. 2008, 2015, Dokas et al. 2013
↑ basal (EDL rat muscle)n.d.Whitfield et al. 2017

FAU in skeletal muscle
n.d.
↑ in C2C12 myotubesMiklosz et al. 2016Intramyocellular lipid accumulation in C2C12 myotubesn.d.
↓ after palmitate incubationMiklosz et al. 2017 Intramyocellular DAG in C2C12 myotubesn.d.
↓ after palmitate incubationMiklosz et al. 2017FAT/CD36 expression↑ red Quadriceps rat muscle

↔ white Quadriceps rat muscle
↑ in C2C12 myotubesMiklosz et al. 2016, Whitfield et al. 2017FATP-1 expressionn.d.
↔ in C2C12 myotubesMiklosz et al. 2016FATP-4 expressionn.d.
↔ in C2C12 myotubesMiklosz et al. 2016FABPpm expressionn.d.
↑ in C2C12 myotubesMiklosz et al. 2016Mitochondrial β-HAD activity↔ in rat skeletal muscle
n.d.Whitfield et al. 2017FAO in pancreatic islets↑ basal (mouse islets)
n.d.Stermann et al. 2018
Figure 1
Figure 1

Domain structures and phosphorylation sites in TBC1D1 and TBC1D4. The two related proteins, TBC1D1 and TBC1D4, contain two amino-terminal PTB domains, a Ca+/calmodulin-binding domain (CBD) and a catalytic RabGAP domain. Both TBC1D1 and TBC1D4 are phosphorylated at multiple Ser/Thr residues in response to insulin, IGF-1 and contraction/exercise by AKT and AMPK.

Citation: Journal of Molecular Endocrinology 64, 1; 10.1530/JME-19-0143

In primary myotubes, in vitro electric pulse stimulation (EPS) mimics at least in part biological adaptions to endurance exercise (Nedachi et al. 2008). Similar to in vivo exercise, long-term EPS (≥24 h, low frequency) induces glucose uptake and oxidation in response to AMPK activation via increased TBC1D1 phosphorylation (Nedachi et al. 2008). In contrast, short-term EPS (≤8 h) treatment in fact leads to increased AMPK phosphorylation only at low frequency (≤5 Hz), whereas glucose uptake is increased at low and high frequency (≥30 Hz) (Goto-Inoue et al. 2016, Nikolic et al. 2017). However, no changes in TBC1D1 phosphorylation were observed after short-term EPS at both frequencies (Nikolic et al. 2017). In human skeletal muscle from lean subjects, acute exercise followed by insulin stimulation potentiated phosphorylation of TBC1D4 at Ser318, Ser341, Ser588, Ser704, Ser751 and Thr642 (Vind et al. 2011, Pehmoller et al. 2012). In contrast, human primary myotubes that were exposed to in vitro contraction via EPS increased insulin-mediated phosphorylation of Thr642, Ser341 and Ser588, but could not potentiate the phosphorylation of Ser318 and Ser704. Therefore it is difficult to deduce additive stimulatory effects of insulin and contraction on TBC1D4 phosphorylation (Park et al. 2019). Myotubes from lean individuals that were first subjected to EPS displayed elevated TBC1D4 phosphorylation in response to insulin stimulation compared to obese persons. Therefore, in vitro contractile activity is able to potentiate insulin-stimulated TBC1D4 phosphorylation and improves insulin action, but to a lesser extent with cells from severely obese participants (Park et al. 2019).

TBC1D1 signaling is important for glucose uptake during recovery after acute exercise training

So far, it is not possible to deduce a specific role of each of the two RabGAPs in exercise signaling in skeletal muscle, since both exhibit phosphorylation sites that are exclusively phosphorylated in response to exercise (Treebak et al. 2014). In muscle-specific AMPKα1α2 (mdAMPKα1α2)-knockout mice where both α-subunits were abrogated, contraction-mediated glucose uptake into skeletal muscle was still normal, although TBC1D1 phosphorylation is severely impaired. This indicates that TBC1D1 may have a greater impact on glucose uptake during recovery after exercise than throughout the actual exercise training. However, in muscles from WT mice, TBC1D1 phosphorylation is increased 30 min and 1 h after in situ contraction and enhanced glucose uptake has been observed 1 h after the end of the contraction (Kjøbsted et al. 2019b).

TBC1D4 enhances skeletal muscle insulin sensitivity and insulin-dependent glucose transport several hours after a single bout of exercise

Genetic evidence suggests that TBC1D4 is required to enhance insulin sensitivity in skeletal muscle after exercise. Three hours after contraction or 6 h after AICAR stimulation, insulin-stimulated glucose uptake was increased in muscles from WT but not from Tbc1d4-deficient mice (Kjøbsted et al. 2019a). Similarly, in rat skeletal muscle, TBC1D4 phosphorylation was enhanced after a single bout of exercise, resulting in increased insulin-dependent glucose transport for several hours post exercise (Arias et al. 2007). The enhanced insulin sensitivity in muscle after exercise was associated with increased insulin-stimulated phosphorylation of TBC1D4 but not TBC1D1 (Arias et al. 2007, Funai et al. 2009, Pehmoller et al. 2012, Kjøbsted et al. 2015, 2019b).

Exercise has been shown to induce increased insulin-stimulated glucose uptake in skeletal muscle fibers type I, IIA, IIB, and IIBX but not IIX fibers, leading to the hypothesis whether exercise effects on TBC1D4 phosphorylation correspond to fiber type-selective exercise effects on insulin-stimulated glucose uptake (Cartee et al. 2016). Immediately after exercise, phosphorylation of TBC1D4 at Ser704 has been observed in each fiber type. However, in insulin-stimulated muscles 3.5 h post exercise, phosphorylation of TBC1D4 at Thr642 and Ser704 was only observed in skeletal muscle fiber type I, IIA, IIB, and IIBX, but not in IIX fibers. These results support the hypothesis that enhanced insulin-stimulated phosphorylation of TBC1D4 is linked to elevated insulin-stimulated glucose uptake post exercise in a fiber type-specific manner (Wang et al. 2019).

RabGAPs may regulate translocation of fatty acid transporter to the plasma membrane in response to contraction

Muscle contraction induces FAT/CD36 translocation to the plasma membrane and increases import of NEFAs (Jordy & Kiens 2014). In the resting state, a direct mechanistic link between AMPK activation and FAT/CD36 translocation has been proposed, since AICAR stimulation induced an increase in fatty acid uptake in skeletal muscle. More specifically, this AMPK-induced lipid oxidation is reduced in Cd36-knockout mice compared to WT littermates (Bonen et al. 2007). Moreover, FAT/CD36 translocation to the cell membrane is shown to be blunted after AICAR stimulation in transgenic AMPK kinase dead (AMPK KD) mice in non-exercising conditions, indicating that AMPK represents an important regulator of FAT/CD36 translocation under specific physiological conditions (Jeppesen et al. 2011). AMPK is a heterotrimeric protein that consists of catalytic α-subunit and regulatory β- and γ-subunits (Hardie & Sakamoto 2006). The α-subunit is responsible for AMPK activation due to phosphorylation of Thr172 residue (McBride & Hardie 2009). AMPKα KD mice overexpress a kinase-dead mutant of AMPK α2-protein, leading to a suppressed AMPKα2 activity. Interestingly, exercise induced an equal increase in cell-surface membrane FAT/CD36 content in skeletal muscle from WT and AMPKα2 KD2 KDa mice (Jeppesen et al. 2011). This result supports an AMPK-independent mechanism in the FAT/CD36 translocation to the cell surface (Jeppesen et al. 2011). As direct AMPK phosphorylation targets, TBC1D1 and TBC1D4 represent a probable link between contractive stimulation and the uptake of fatty acids, for instance by regulating FAT/CD36 translocation.

Muscle contraction has a stimulatory effect on the translocation of FABPpm, FATP-1 and FATP-4 transporters as well (Jain et al. 2009), whereby FATP-1 translocation is also induced by insulin stimulation (Jain et al. 2015). Moreover, a decrease of both, FAT/CD36 and FABPpm protein abundance, is observed in a mouse model lacking both AMPKα1 and -α2 in skeletal muscle (AMPKα1α2 mdKO) under sedentary and trained conditions (Fentz et al. 2015). In AMPKα1α2 mdKO, TBC1D1 phosphorylation at the AMPK-dependent phosphorylation site Ser237 is blunted in response to contraction compared to WT littermates. These changes may contribute to an impairment of fatty acid cellular membrane transport and therefore TBC1D1 Ser237 may account to FAT/CD36 and FABPpm translocation and fatty acid metabolism in response to exercise (Fentz et al. 2015). These results indicate that in mice exercise- and contraction-induced fatty acid utilization in skeletal muscle is disturbed only when both AMPKα1 and AMPKα2 subunits are ablated, due to missing phosphorylation of TBC1D1 Ser237.

TBC1D4 signaling is involved in the exercise-mediated improvements on lipid-induced insulin resistance

As already mentioned in a chapter above, accumulation of toxic lipid intermediates such as DAGs in skeletal muscle impair muscular insulin sensitivity by inhibiting the insulin signaling cascade and consequently, GLUT4 translocation (Ragheb et al. 2009, Boucher et al. 2014, Morales et al. 2017). Exercise has a prophylactic effect on lipid-induced insulin resistance. Even a single bout of exercise has the ability to prevent lipid-induced impairments in whole-body glucose tolerance (Schenk & Horowitz 2007). The prophylactic effect of exercise on lipid-induced insulin resistance may involve TBC1D4 signaling. After lipid-induced insulin resistance in exercised human, prior exercise normalized insulin-stimulated glucose uptake to the level that has been observed in the resting control leg that received saline injection (Pehmoller et al. 2012). Phosphorylation of TBC1D4 at Ser341 was impaired after lipid-induced insulin resistance in exercise human. The impairment could not be fully rescued after a single bout of exercise. On the other hand, neither prior exercise nor intralipid infusion affected basal and insulin-induced phosphorylation of TBC1D1 at Thr596 and Ser237 (Pehmoller et al. 2012). These results indicate that the signaling nexus TBC1D4 could play a potential role in the enhanced insulin action observed after a single bout of exercise (Treebak et al. 2009, Pehmoller et al. 2012).

RabGAPs control skeletal muscle development

IGFBP-2 activation leads to enhanced insulin-stimulated glucose uptake in human skeletal myotubes via AKT and AMPK activation

Insulin-like growth factor-binding protein-2 (IGFBP-2) belongs to a family of seven structurally binding proteins that regulate the bioavailability of IGF-1 (Russo et al. 2005). Reduced IGFBP-2 plasma levels are associated with higher fasting glucose levels and reduced insulin sensitivity in humans (Heald et al. 2006) and therefore IGFBP-2 may play a role in the development of insulin resistance and T2DM. Treatment of 3T3-L1 adipocytes with IGFBP-2 stimulates glucose uptake in a synergistic activation of AKT and AMPK with subsequently increased phosphorylation of TBC1D1 at the AMPK-dependent phosphorylation site Ser237 (Assefa et al. 2017). Neither AKT-dependent TBC1D1 phosphorylation sites, nor the phosphorylation state of TBC1D4 were measured. According to these data, it seems that IGFBP-2 activates the insulin-responsive phosphorylation sites of AKT at Ser473 and AMPK at Thr172 (Yau et al. 2014, Assefa et al. 2017).

TBC1D1 signaling affects plasma IGF-1 levels

IGF-1 exhibits structural homology to proinsulin and plays a critical role in proliferation and differentiation of skeletal muscle and adipocytes (Rinderknecht & Humbel 1978, Smith et al. 1988). Insulin-like metabolic effects are induced by IGF-1 in both skeletal muscle and adipose tissue (Monzavi & Cohen 2002). Mice that exhibit a Tbc1d1 Ser231Ala knockin mutation that prevents AMPK-dependent phosphorylation of TBC1D1 at Ser231 display higher plasma IGF-1 levels (Chen et al. 2016). This phosphorylation site is necessary to mediate 14-3-3 interaction with TBC1D1 in response to AMPK stimulation. 14-3-3 proteins interact with phosphorylated serine and threonine residues in TBC1D1 and TBC1D4 to support glucose uptake (Ramm et al. 2006). In Tbc1d1 Ser231Ala knockin mice, where AMPK-dependent phosphorylation at Ser231 and subsequent 14-3-3 interaction are inhibited, glucose uptake in response to AICAR-stimulation is reduced (Chen et al. 2016). TBC1D1 may mediate IGF-1 secretion, as TBC1D1 is located on IGF-1 storage vesicles (Chen et al. 2016). In Tbc1d1 Ser231Ala knockin mice, endocrinal and paracrinal/autocrinal IGF-1 secretion is enhanced in a Rab8a-dependent manner, resulting in a hypersecretion of IGF-1 that causes increased activation of the AKT-mammalian target of rapamycin (mTOR) pathway (Chen et al. 2016). These data provide evidence that TBC1D1 signaling interacts with the AKT-mTOR pathway via IGF-1 signaling (Fig. 2).

Figure 2
Figure 2

RabGAPs in skeletal muscle signaling. The RabGAPs TBC1D1 and TBC1D4 are crucial mediators in skeletal muscle signaling in response to insulin, IGF-1 and contraction. After binding of insulin or IGF-1 to its receptor, the IRS-PI3K-AKT signaling cascade is activated, leading to phosphorylation of TBC1D1 and TBC1D4 and subsequent translocation of GLUT4 from storage vesicles (GSV) to the plasma membrane. Phosphorylation of TBC1D4 may also regulate trafficking of fatty acid transporters FAT/CD36 and FATPpm. In response to contraction, LKB1 is also activated, leading to phosphorylation of AMPK and stimulation of fatty acid oxidation in mitochondria. TBC1D1 is associated with IGF-1 containing vesicles and might be involved in secretion of the hormone in skeletal muscle, where IGF-1 act in a paracrine/autocrine manner promoting skeletal muscle growth, differentiation and protein synthesis through the mTORC1 pathway (Geraghty et al. 2007, Taylor et al. 2008, Zhou et al. 2008, Peck et al. 2009, Funai et al. 2010, Guerra et al. 2010, Treebak et al. 2010, Jessen et al. 2011, Schweitzer et al. 2012, Castorena et al. 2014, Wang et al. 2018).

Citation: Journal of Molecular Endocrinology 64, 1; 10.1530/JME-19-0143

RabGAPs are linked with skeletal muscle development via IR and IGF1R signal transduction

Ablation of one or both RabGAPs in mice did not result in substantial changes in lean mass (Chadt et al. 2015). However, in states of strongly altered muscle mass changes in TBC1D1/TBC1D4 abundance and/or signaling have been observed. Both, insulin receptor (IR) and the IGF-1 receptor (IGF1R) signaling are playing a role in muscle growth and glucose homeostasis. Ablation of IR and IGF1R specifically in murine skeletal muscle (MIGIRKO) led to a >60% decrease in muscle mass, severe muscle atrophy with spinal deformities and obvious kyphosis (O’Neill et al. 2015). MIGIRKO mice exhibit hypoglycemia under fasted conditions and increased basal glucose uptake due to increased expression and translocation of GLUT4, indicating that whole-body adaptions like increased basal glucose uptake into scWAT are responsible for normal glucose and insulin tolerance. It has been hypothesized that alternative tyrosine kinases may activate the insulin receptor substrate (IRS)-phosphoinositide 3-kinase (PI3K)-AKT pathway in the absence of IR and IGF1R. Indeed, total EGF receptor (EGFR) levels are increased in MIGIRKO muscles, which may contribute to the observed increase in AKT phosphorylation. As a direct result of the elevated AKT activation, basal phosphorylation of TBC1D4 (Thr642) is increased in EDL and Soleus from fasted MIGIRKO mice (O’Neill et al. 2015). Despite an enhanced AMPK activation, TBC1D1 phosphorylation is not altered and TBC1D1 abundance is decreased (O’Neill et al. 2015). Increased AMPK phosphorylation might contribute to the decreased muscle mass in MIGIRKO mice (Bolster et al. 2002). Reduced TBC1D1 expression correlates with less muscle growth while increased TBC1D4 signaling seems to be responsible for enhanced basal glucose uptake in response to increased AKT activation in the basal state.

TBC1D4 is associated with skeletal muscle growth, as TBC1D4 signaling is enhanced upon inactivation of the myokine myostatin (Kocsis et al. 2017). Myostatin has been shown to be a negative regulator of muscle growth and development that inhibits proliferation and differentiation in myogenic cells as well as protein synthesis in existing muscle fibers (Chen & Lee 2016). Mice that exhibit a loss of myostatin activity displayed hypermuscular changes and increased muscle weight. Moreover, phosphorylation of TBC1D4 (Thr642) is higher in comparison to WT littermates. However, neither phosphorylation state nor protein abundance of TBC1D1 were determined in mice exhibiting loss of myostatin activity. Therefore the hypermuscular effects could also be mediated by TBC1D1, and TBC1D4 is rather responsible for the improvements in glucose tolerance as AKT phosphorylation is increased as well (Kocsis et al. 2017).

Thus, even though both RabGAPs are associated with states of altered skeletal muscle growth, the causal contribution of TBC1D1 and TBC1D4 in skeletal muscle development remains to be determined. It is possible that RabGAP signaling primarily supports altered energy substrate metabolism of the growing muscle.

Moreover, while fiber type differences have a strong impact on skeletal muscle development (Schiaffino & Reggiani 2011), the role of RabGAPs in fiber type-specific development remains to be established.

TBC1D1 is associated with increased muscle mass in livestock animals

From genetic studies of livestock it is known that TBC1D1 is closely associated with meat production and, as a consequence, with skeletal muscle development. A strong quantitative trait locus (QTL) for growth in chicken has been identified in the genomic region containing TBC1D1 (Rubin et al. 2010). Moreover, specific SNPs in the chicken TBC1D1 gene are associated with body weight (g.69340070CNT) and leg muscle weight (g.69307744CNT) (Wang et al. 2014). During chicken development, Tbc1d1 mRNA increases in thigh muscle until week 10 and is unaltered afterward, whereas in breast muscle Tbc1d1 mRNA expression is generally unaltered during chicken development (Peng et al. 2015). These differences may occur due to the physiology of muscle composition, as the chicken thigh is more oxidative, compared to the more glycolytic breast and therefore the latter more closely resembles the glycolytic EDL (Williamson et al. 2006). However, muscle weight has not been measured in the latter study; therefore, it is unclear whether Tbc1d1 mRNA expression equally correlates with growth in different types of muscle. In addition, a variant (g.219G>A) in the porcine TBC1D1 gene was associated with meat production in Italian Large White and Italian Duroc breeds, whereas another variant (c.214G>A) was associated with postnatal growth traits in rabbits (Fontanesi et al. 2011, 2012, Yang et al. 2013). The latter studies however did not resolve the contribution of the variants to fat deposition and muscle mass. Despite the genetic evidence for an association of TBC1D1 with muscle growth, it remains to be further investigated whether TBC1D1 signaling induces muscle growth or hypertrophy activates TBC1D1 expression and signaling.

Conclusion

In this review, we summarize studies of the two RabGAPs TBC1D1 and TBC1D4 in skeletal muscle function, development and exercise physiology. The importance of TBC1D1 and TBC1D4 for GLUT4-mediated glucose uptake is well established. However, the mechanisms how these RabGAPs regulate lipid utilization in skeletal muscle are now well understood. In analogy to the regulation of glucose transporters, TBC1D1 and TBC1D4 might regulate RabGTPase-dependent trafficking of fatty acid transporters.

While both RabGAPs maybe involved in the exercise-stimulated glucose uptake where deficiency impairs exercise endurance, the individual contribution of each RabGAP is not yet known. TBC1D1 may have a greater impact on glucose uptake during recovery after exercise than throughout the actual exercise training, whereas there is genetic evidence of TBC1D4 signaling to enhance muscle insulin sensitivity following contraction. Moreover, genetic cross species studies indicate that TBC1D1, the evolutionary more ancient isoform, is closely associated with meat production and thus muscle development, implicating an essential function of this RabGAP in muscle biology.

In summary, the contributions of each of the two RabGAPs to skeletal muscle function and development are complex and not restricted to purely metabolic signaling pathways. There is rising evidence for a diversified role of TBC1D1 and TBC1D4 in the distinct processes, and it is clear that up to today, we are far from understanding the whole picture.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

This work was supported by the Ministry of Innovation, Science and Research of the State of North Rhine-Westphalia (MIWF NRW) and the German Federal Ministry of Health (BMG) and was funded in part by grants from the Deutsche Forschungsgemeinschaft (SFB1116 to H A; CH1659 to A C) and the EFSD/Novo Nordisk program (to H A).

Acknowledgement

The authors would like to thank Dr Samaneh Eickelschulte for support in preparing the manuscript.

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    Domain structures and phosphorylation sites in TBC1D1 and TBC1D4. The two related proteins, TBC1D1 and TBC1D4, contain two amino-terminal PTB domains, a Ca+/calmodulin-binding domain (CBD) and a catalytic RabGAP domain. Both TBC1D1 and TBC1D4 are phosphorylated at multiple Ser/Thr residues in response to insulin, IGF-1 and contraction/exercise by AKT and AMPK.

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    RabGAPs in skeletal muscle signaling. The RabGAPs TBC1D1 and TBC1D4 are crucial mediators in skeletal muscle signaling in response to insulin, IGF-1 and contraction. After binding of insulin or IGF-1 to its receptor, the IRS-PI3K-AKT signaling cascade is activated, leading to phosphorylation of TBC1D1 and TBC1D4 and subsequent translocation of GLUT4 from storage vesicles (GSV) to the plasma membrane. Phosphorylation of TBC1D4 may also regulate trafficking of fatty acid transporters FAT/CD36 and FATPpm. In response to contraction, LKB1 is also activated, leading to phosphorylation of AMPK and stimulation of fatty acid oxidation in mitochondria. TBC1D1 is associated with IGF-1 containing vesicles and might be involved in secretion of the hormone in skeletal muscle, where IGF-1 act in a paracrine/autocrine manner promoting skeletal muscle growth, differentiation and protein synthesis through the mTORC1 pathway (Geraghty et al. 2007, Taylor et al. 2008, Zhou et al. 2008, Peck et al. 2009, Funai et al. 2010, Guerra et al. 2010, Treebak et al. 2010, Jessen et al. 2011, Schweitzer et al. 2012, Castorena et al. 2014, Wang et al. 2018).

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