scholarly journals Six1 Promotes Skeletal Muscle Thyroid Hormone Response through Regulation of the MCT10 Transporter

2021 ◽  
Author(s):  
John Girgis ◽  
Dabo Yang ◽  
Imane Chakroun ◽  
Yubing Liu ◽  
Alexandre Blais
Keyword(s):  
Skeletal Muscle ◽  
Thyroid Hormone ◽  
Tibialis Anterior ◽  
Molecular Mechanisms ◽  
Thyroid Hormone Receptor ◽  
Muscle Metabolism ◽  
Loss Of Function ◽  
Transcriptional Enhancer ◽  
Fast Twitch Muscle ◽  
Fast Twitch

AbstractThe Six1 transcription factor is implicated in controlling the development of several tissue types, notably skeletal muscle. Six1 also contributes to muscle metabolism and its activity is associated with the fast-twitch, glycolytic phenotype. Six1 regulates the expression of certain genes of the fast muscle program by directly stimulating their transcription or indirectly acting through a long non-coding RNA. Under the hypothesis that additional mechanisms of action might be at play, a combined analysis of gene expression profiling and genome-wide location analysis data was performed. The Slc16a10 gene, encoding the thyroid hormone transmembrane transporter MCT10, was identified as a gene with a transcriptional enhancer directly bound by Six1 and requiring Six1 activity for full expression in adult mouse tibialis anterior, a predominantly fast-twitch muscle. Of the various thyroid hormone transporters, MCT10 mRNA was found to be the most abundant in skeletal muscle, and to have a stronger expression in fast-twitch compared to slow-twitch muscle groups. Loss-of-function of MCT10 in the tibialis anterior recapitulated the effect of Six1 on the expression of fast-twitch muscle genes and led to lower activity of a thyroid hormone receptor-dependent reporter gene. These results shed light on the molecular mechanisms controlling the tissue expression profile of MCT10 and identify modulation of the thyroid hormone signaling pathway as an additional mechanism by which Six1 influences skeletal muscle metabolism.

scholarly journals Six1 promotes skeletal muscle thyroid hormone response through regulation of the MCT10 transporter

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
John Girgis ◽  
Dabo Yang ◽  
Imane Chakroun ◽  
Yubing Liu ◽  
Alexandre Blais
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Thyroid Hormone ◽  
Tibialis Anterior ◽  
Molecular Mechanisms ◽  
Thyroid Hormone Receptor ◽  
Muscle Metabolism ◽  
Loss Of Function ◽  
Fast Twitch Muscle ◽  
Fast Twitch

Abstract Background The Six1 transcription factor is implicated in controlling the development of several tissue types, notably skeletal muscle. Six1 also contributes to muscle metabolism and its activity is associated with the fast-twitch, glycolytic phenotype. Six1 regulates the expression of certain genes of the fast muscle program by directly stimulating their transcription or indirectly acting through a long non-coding RNA. We hypothesized that additional mechanisms of action of Six1 might be at play. Methods A combined analysis of gene expression profiling and genome-wide location analysis data was performed. Results were validated using in vivo RNA interference loss-of-function assays followed by measurement of gene expression by RT-PCR and transcriptional reporter assays. Results The Slc16a10 gene, encoding the thyroid hormone transmembrane transporter MCT10, was identified as a gene with a transcriptional enhancer directly bound by Six1 and requiring Six1 activity for full expression in adult mouse tibialis anterior, a predominantly fast-twitch muscle. Of the various thyroid hormone transporters, MCT10 mRNA was found to be the most abundant in skeletal muscle, and to have a stronger expression in fast-twitch compared to slow-twitch muscle groups. Loss-of-function of MCT10 in the tibialis anterior recapitulated the effect of Six1 on the expression of fast-twitch muscle genes and led to lower activity of a thyroid hormone receptor-dependent reporter gene. Conclusions These results shed light on the molecular mechanisms controlling the tissue expression profile of MCT10 and identify modulation of the thyroid hormone signaling pathway as an additional mechanism by which Six1 influences skeletal muscle metabolism.

Thyroid hormone (T3) rapidly activates p38 and AMPK in skeletal muscle in vivo

2008 ◽  
Vol 104 (1) ◽  
pp. 178-185 ◽  
Author(s):  
Isabella Irrcher ◽  
Donald R. Walkinshaw ◽  
Treacey E. Sheehan ◽  
David A. Hood
Keyword(s):  
Skeletal Muscle ◽  
Thyroid Hormone ◽  
Dna Binding ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Kinase Phosphorylation ◽  
Fast Twitch

Thyroid hormone (T3) regulates the function of many tissues within the body. The effects of T3 have largely been attributed to the modulation of thyroid hormone receptor-dependent gene transcription. However, nongenomic actions of T3 via the initiation of signaling events are emerging in a number of cell types. This study investigated the ability of short-term T3 treatment to phosphorylate and, therefore, activate signaling proteins in rat tissues in vivo. The kinases investigated included p38, AMP-activated protein kinase (AMPK), and extracellular signal-regulated kinase (ERK) 1/2. Following 2 h of T3 treatment, p38 and AMPK phosphorylation was increased in both the slow-twitch soleus and the fast-twitch plantaris muscles. In contrast, ERK1/2 was not activated in either muscle type. Neither p38 nor AMPK was affected in heart. However, AMPK activation was decreased by T3 in liver. ERK1/2 activation was decreased by T3 in heart, but increased in liver. Possible downstream consequences of T3-induced kinase phosphorylation were investigated by measuring cAMP response element binding protein (CREB) and thyroid hormone receptor DNA binding, as well as peroxisome proliferator-activated receptor-α coactivator-1 mRNA levels. Protein DNA binding to the cAMP or thyroid hormone response elements was unaltered by T3. However, peroxisome proliferator-activated receptor-α coactivator-1 mRNA expression was increased following 12 h of T3 treatment in soleus. These data are the first to characterize the effects of T3 treatment on kinase phosphorylation in vivo. We show that T3 rapidly modifies kinase activity in a tissue-specific fashion. Moreover, the T3-induced phosphorylation of p38 and AMPK in both slow- and fast-twitch skeletal muscles suggests that these events may be important in mediating hormone-induced increases in mitochondrial biogenesis in skeletal muscle.

scholarly journals Desethylamiodarone antagonizes the effect of thyroid hormone at the molecular level

2001 ◽  
pp. 59-64 ◽  
Author(s):  
F Bogazzi ◽  
L Bartalena ◽  
S Brogioni ◽  
A Burelli ◽  
F Raggi ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Molecular Mechanisms ◽  
Thyroid Hormone Receptor ◽  
Molecular Level ◽  
Inhibitory Effect ◽  
Mobility Shift ◽  
Down Regulation ◽  
Nih3t3 Cells ◽  
Peripheral Tissues

OBJECTIVE: To evaluate the molecular mechanisms of the inhibitory effects of amiodarone and its active metabolite, desethylamiodarone (DEA) on thyroid hormone action. MATERIALS AND METHODS: The reporter construct ME-TRE-TK-CAT or TSHbeta-TRE-TK-CAT, containing the nucleotide sequence of the thyroid hormone response element (TRE) of either malic enzyme (ME) or TSHbeta genes, thymidine kinase (TK) and chloramphenicol acetyltransferase (CAT) was transiently transfected with RSV-TRbeta into NIH3T3 cells. Gel mobility shift assay (EMSA) was performed using labelled synthetic oligonucleotides containing the ME-TRE and in vitro translated thyroid hormone receptor (TR)beta. RESULTS: Addition of 1 micromol/l T4 or T3 to the culture medium increased the basal level of ME-TRE-TK-CAT by 4.5- and 12.5-fold respectively. Amiodarone or DEA (1 micromol/l) increased CAT activity by 1.4- and 3.4-fold respectively. Combination of DEA with T4 or T3 increased CAT activity by 9.4- and 18.9-fold respectively. These data suggested that DEA, but not amiodarone, had a synergistic effect with thyroid hormone on ME-TRE, rather than the postulated inhibitory action; we supposed that this was due to overexpression of the transfected TR into the cells. When the amount of RSV-TRbeta was reduced until it was present in a limited amount, allowing competition between thyroid hormone and the drug, addition of 1 micromol/l DEA decreased the T3-dependent expression of the reporter gene by 50%. The inhibitory effect of DEA was partially due to a reduced binding of TR to ME-TRE, as assessed by EMSA. DEA activated the TR-dependent down-regulation by the negative TSH-TRE, although at low level (35% of the down-regulation produced by T3), whereas amiodarone was ineffective. Addition of 1 micromol/l DEA to T3-containing medium reduced the T3-TR-mediated down-regulation of TSH-TRE to 55%. CONCLUSIONS: Our results demonstrate that DEA, but not amiodarone, exerts a direct, although weak, effect on genes that are regulated by thyroid hormone. High concentrations of DEA antagonize the action of T3 at the molecular level, interacting with TR and reducing its binding to TREs. This effect may contribute to the hypothyroid-like effect observed in peripheral tissues of patients receiving amiodarone treatment.

Alpha-actin and cytochrome c mRNAs in atrophied adult rat skeletal muscle

1988 ◽  
Vol 254 (5) ◽  
pp. C651-C656 ◽  
Author(s):  
P. Babij ◽  
F. W. Booth
Keyword(s):  
Skeletal Muscle ◽  
Cytochrome C ◽  
Muscle Atrophy ◽  
Weight Bearing ◽  
Skeletal Muscle Atrophy ◽  
Rna Content ◽  
Mrna Content ◽  
Fast Twitch Muscle ◽  
Alpha Actin ◽  
Fast Twitch

Specific complementary DNA (cDNA) hybridization probes were used to estimate the levels of alpha-actin and cytochrome c mRNAs and also 18S rRNA in three models of skeletal muscle atrophy. After 7 days of hindlimb suspension, or immobilization, or denervation, protein content decreased 26-32% in all muscles studied except suspended fast-twitch muscle, which lost only half as much protein. alpha-Actin mRNA content decreased 51-66% and cytochrome c mRNA content decreased 42-61% in slow- and fast-twitch muscles in all three models of atrophy. However, total RNA content did not show similar directional changes; RNA content decreased 27-44% in suspended and immobilized muscle but was unchanged in denervated fast-twitch muscle. The results were interpreted to suggest that loss of weight-bearing function of skeletal muscle is a major factor affecting the levels of alpha-actin and cytochrome c mRNAs during muscle atrophy.

Dynamics and Consequences of Potassium Shifts in Skeletal Muscle and Heart During Exercise

2000 ◽  
Vol 80 (4) ◽  
pp. 1411-1481 ◽  
Author(s):  
Ole M. Sejersted ◽  
Gisela Sjøgaard
Keyword(s):  
Skeletal Muscle ◽  
Force Production ◽  
Membrane Conductance ◽  
Cell Swelling ◽  
Modifying Factors ◽  
Fast Twitch Muscle ◽  
T Tubules ◽  
Exercise Induced ◽  
Fast Twitch ◽  
Muscle Excitability

Since it became clear that K+shifts with exercise are extensive and can cause more than a doubling of the extracellular [K+] ([K+]s) as reviewed here, it has been suggested that these shifts may cause fatigue through the effect on muscle excitability and action potentials (AP). The cause of the K+shifts is a transient or long-lasting mismatch between outward repolarizing K+currents and K+influx carried by the Na+-K+pump. Several factors modify the effect of raised [K+]sduring exercise on membrane potential ( Em) and force production. 1) Membrane conductance to K+is variable and controlled by various K+channels. Low relative K+conductance will reduce the contribution of [K+]sto the Em. In addition, high Cl−conductance may stabilize the Emduring brief periods of large K+shifts. 2) The Na+-K+pump contributes with a hyperpolarizing current. 3) Cell swelling accompanies muscle contractions especially in fast-twitch muscle, although little in the heart. This will contribute considerably to the lowering of intracellular [K+] ([K+]c) and will attenuate the exercise-induced rise of intracellular [Na+] ([Na+]c). 4) The rise of [Na+]cis sufficient to activate the Na+-K+pump to completely compensate increased K+release in the heart, yet not in skeletal muscle. In skeletal muscle there is strong evidence for control of pump activity not only through hormones, but through a hitherto unidentified mechanism. 5) Ionic shifts within the skeletal muscle t tubules and in the heart in extracellular clefts may markedly affect excitation-contraction coupling. 6) Age and state of training together with nutritional state modify muscle K+content and the abundance of Na+-K+pumps. We conclude that despite modifying factors coming into play during muscle activity, the K+shifts with high-intensity exercise may contribute substantially to fatigue in skeletal muscle, whereas in the heart, except during ischemia, the K+balance is controlled much more effectively.

scholarly journals Insulin-sensitive regulation of glucose transport and GLUT4 translocation in skeletal muscle of GLUT1 transgenic mice

1998 ◽  
Vol 337 (1) ◽  
pp. 51-57 ◽  
Author(s):  
Garret J. ETGEN ◽  
William J. ZAVADOSKI ◽  
Geoffrey D. HOLMAN ◽  
E. Michael GIBBS
Keyword(s):  
Skeletal Muscle ◽  
Cell Surface ◽  
Transgenic Mice ◽  
Glucose Transport ◽  
Hind Limb ◽  
Glucose Transporter ◽  
Glut4 Translocation ◽  
Transport Activity ◽  
Fast Twitch Muscle ◽  
Fast Twitch

Skeletal muscle glucose transport was examined in transgenic mice overexpressing the glucose transporter GLUT1 using both the isolated incubated-muscle preparation and the hind-limb perfusion technique. In the absence of insulin, 2-deoxy-d-glucose uptake was increased ∼ 3–8-fold in isolated fast-twitch muscles of GLUT1 transgenic mice compared with non-transgenic siblings. Similarly, basal glucose transport activity was increased ∼ 4–14-fold in perfused fast-twitch muscles of transgenic mice. In non-transgenic mice insulin accelerated glucose transport activity ∼ 2–3-fold in isolated muscles and to a much greater extent (∼ 7–20-fold) in perfused hind-limb preparations. The observed effect of insulin on glucose transport in transgenic muscle was similarly dependent upon the technique used for measurement, as insulin had no effect on isolated fast-twitch muscle from transgenic mice, but significantly enhanced glucose transport in perfused fast-twitch muscle from transgenic mice to ∼ 50–75% of the magnitude of the increase observed in non-transgenic mice. Cell-surface glucose transporter content was assessed via 2-N-4-(l-azi-2,2,2-trifluoroethyl)benzoyl-1,3-bis-(d -mannos-4-yloxy)-2-propylamine photolabelling methodology in both isolated and perfused extensor digitorum longus (EDL). Cell-surface GLUT1 was enhanced by as much as 70-fold in both isolated and perfused EDL of transgenic mice. Insulin did not alter cell-surface GLUT1 in either transgenic or non-transgenic mice. Basal levels of cell-surface GLUT4, measured in either isolated or perfused EDL, were similar in transgenic and non-transgenic mice. Interestingly, insulin enhanced cell-surface GLUT4 ∼ 2-fold in isolated EDL and ∼ 6-fold in perfused EDL of both transgenic and non-transgenic mice. In summary, these results reveal differences between isolated muscle and perfused hind-limb techniques, with the latter method showing a more robust responsiveness to insulin. Furthermore, the results demonstrate that muscle overexpressing GLUT1 has normal insulin-induced GLUT4 translocation and the ability to augment glucose-transport activity above the elevated basal rates.

scholarly journals Thyroid Hormone Receptor α Plays an Essential Role in Male Skeletal Muscle Myoblast Proliferation, Differentiation, and Response to Injury

Endocrinology ◽  
2016 ◽  
Vol 157 (1) ◽  
pp. 4-15 ◽  
Author(s):  
Anna Milanesi ◽  
Jang-Won Lee ◽  
Nam-Ho Kim ◽  
Yan-Yun Liu ◽  
An Yang ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Essential Role ◽  
Mutant Mouse ◽  
Thyroid Hormone Receptor ◽  
Myogenic Differentiation ◽  
Myoblast Differentiation ◽  
Primary Myoblasts ◽  
Myoblast Proliferation

Abstract Thyroid hormone plays an essential role in myogenesis, the process required for skeletal muscle development and repair, although the mechanisms have not been established. Skeletal muscle develops from the fusion of precursor myoblasts into myofibers. We have used the C2C12 skeletal muscle myoblast cell line, primary myoblasts, and mouse models of resistance to thyroid hormone (RTH) α and β, to determine the role of thyroid hormone in the regulation of myoblast differentiation. T3, which activates thyroid hormone receptor (TR) α and β, increased myoblast differentiation whereas GC1, a selective TRβ agonist, was minimally effective. Genetic approaches confirmed that TRα plays an important role in normal myoblast proliferation and differentiation and acts through the Wnt/β-catenin signaling pathway. Myoblasts with TRα knockdown, or derived from RTH-TRα PV (a frame-shift mutation) mice, displayed reduced proliferation and myogenic differentiation. Moreover, skeletal muscle from the TRα1PV mutant mouse had impaired in vivo regeneration after injury. RTH-TRβ PV mutant mouse model skeletal muscle and derived primary myoblasts did not have altered proliferation, myogenic differentiation, or response to injury when compared with control. In conclusion, TRα plays an essential role in myoblast homeostasis and provides a potential therapeutic target to enhance skeletal muscle regeneration.

scholarly journals Effect of glucocorticoid excess on skeletal muscle and heart protein synthesis in adult and old rats

1998 ◽  
Vol 79 (3) ◽  
pp. 297-304 ◽  
Author(s):  
Isabelle Savary ◽  
Elisabeth Debras ◽  
Dominique Dardevet ◽  
Claire Sornet ◽  
Pierre Capitan ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Food Intake ◽  
Tibialis Anterior ◽  
Muscle Wasting ◽  
Recovery Period ◽  
Disease States ◽  
Old Rats ◽  
Fast Twitch

This study was carried out to analyse glucocorticoid-induced muscle wasting and subsequent recovery in adult (6-8 months) and old (18-24 months) rats because the increased incidence of various disease states results in hypersecretion of glucocorticoids in ageing. Adult and old rats received dexamethasone in their drinking water for 5 or 6 d and were then allowed to recover for 3 or 7 d. As dexamethasone decreased food intake, all groups were pair-fed to dexamethasonetreated old rats (i.e. the group that had the lowest food intake). At the end of the treatment, adult and old rats showed significant increases in blood glucose and plasma insulin concentrations. This increase disappeared during the recovery period. Protein synthesis of different muscles was assessed in vivo by a flooding dose of [13C]valine injected subcutaneously 50 min before slaughter. Dexamethasone induced a significant decrease in protein synthesis in fast-twitch glycolytic and oxidative glycolytic muscles (gastrocnemius, tibialis anterior, extensor digitorum longus). The treatment affected mostly ribosomal efficiency. Adult dexamethasone-treated rats showed an increase in protein synthesis compared with their pair-fed controls during the recovery period whereas old rats did not. Dexamethasone also significantly decreased protein synthesis in the predominantly oxidative soleus muscle but only in old rats, and increased protein synthesis in the heart of adult but not of old rats. Thus, in skeletal muscle, the catabolic effect of dexamethasone is maintained or amplified during ageing whereas the anabolic effect in heart is depressed. These results are consistent with muscle atrophy occurring with ageing.

scholarly journals Biomechanical Properties of the Sarcolemma and Costameres of Skeletal Muscle Lacking Desmin

2021 ◽  
Vol 12 ◽  
Author(s):  
Karla P. Garcia-Pelagio ◽  
Robert J. Bloch
Keyword(s):  
Skeletal Muscle ◽  
Lateral Force ◽  
Biomechanical Properties ◽  
Contractile Force ◽  
Contractile Apparatus ◽  
Force Transmission ◽  
Fast Twitch Muscle ◽  
Intracellular Organelles ◽  
Time Required ◽  
Fast Twitch

Intermediate filaments (IFs), composed primarily by desmin and keratins, link the myofibrils to each other, to intracellular organelles, and to the sarcolemma. There they may play an important role in transfer of contractile force from the Z-disks and M-lines of neighboring myofibrils to costameres at the membrane, across the membrane to the extracellular matrix, and ultimately to the tendon (“lateral force transmission”). We measured the elasticity of the sarcolemma and the connections it makes at costameres with the underlying contractile apparatus of individual fast twitch muscle fibers of desmin-null mice. By positioning a suction pipet to the surface of the sarcolemma and applying increasing pressure, we determined the pressure at which the sarcolemma separated from nearby sarcomeres, Pseparation, and the pressure at which the isolated sarcolemma burst, Pbursting. We also examined the time required for the intact sarcolemma-costamere-sarcomere complex to reach equilibrium at lower pressures. All measurements showed the desmin-null fibers to have slower equilibrium times and lower Pseparation and Pbursting than controls, suggesting that the sarcolemma and its costameric links to nearby contractile structures were weaker in the absence of desmin. Comparisons to earlier values determined for muscles lacking dystrophin or synemin suggest that the desmin-null phenotype is more stable than the former and less stable than the latter. Our results are consistent with the moderate myopathy seen in desmin-null muscles and support the idea that desmin contributes significantly to sarcolemmal stability and lateral force transmission.

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