Overexpression of IGF-I in skeletal muscle of transgenic mice does not prevent unloading-induced atrophy

1998 ◽  
Vol 275 (3) ◽  
pp. E373-E379 ◽  
Author(s):  
David S. Criswell ◽  
Frank W. Booth ◽  
Franco DeMayo ◽  
Robert J. Schwartz ◽  
Scott E. Gordon ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Transgenic Mice ◽  
Weight Bearing ◽  
Mrna Level ◽  
Hindlimb Unloading ◽  
Skeletal Muscle Atrophy ◽  
Igf I ◽  
Fast Twitch Muscle ◽  
High Level ◽  
Fast Twitch

This study examined the association between local insulin-like growth factor I (IGF-I) overexpression and atrophy in skeletal muscle. We hypothesized that endogenous skeletal muscle IGF-I mRNA expression would decrease with hindlimb unloading (HU) in mice, and that transgenic mice overexpressing human IGF-I (hIGF-I) specifically in skeletal muscle would exhibit less atrophy after HU. Male transgenic mice and nontransgenic mice from the parent strain (FVB) were divided into four groups ( n = 10/group): 1) transgenic, weight-bearing (IGF-I/WB); 2) transgenic, hindlimb unloaded (IGF-I/HU); 3) nontransgenic, weight-bearing (FVB/WB); and 4) nontransgenic, hindlimb unloaded (FVB/HU). HU groups were hindlimb unloaded for 14 days. Body mass was reduced ( P < 0.05) after HU in both IGF-I (−9%) and FVB mice (−13%). Contrary to our hypothesis, we found that the relative abundance of mRNA for the endogenous rodent IGF-I (rIGF-I) was unaltered by HU in the gastrocnemius (GAST) muscle of wild-type FVB mice. High-level expression of hIGF-I peptide and mRNA was confirmed in the GAST and tibialis anterior (TA) muscles of the transgenic mice. Nevertheless, masses of the GAST and TA muscles were reduced ( P < 0.05) in both FVB/HU and IGF-I/HU groups compared with FVB/WB and IGF-I/WB groups, respectively, and the percent atrophy in mass of these muscles did not differ between FVB and IGF-I mice. Therefore, skeletal muscle atrophy may not be associated with a reduction of endogenous rIGF-I mRNA level in 14-day HU mice. We conclude that high local expression of hIGF-I mRNA and peptide in skeletal muscle alone cannot attenuate unloading-induced atrophy of fast-twitch muscle in mice.

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.

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.

Role for IκBα, but not c-Rel, in skeletal muscle atrophy

2007 ◽  
Vol 292 (1) ◽  
pp. C372-C382 ◽  
Author(s):  
Andrew R. Judge ◽  
Alan Koncarevic ◽  
R. Bridge Hunter ◽  
Hsiou-Chi Liou ◽  
Robert W. Jackman ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Target Genes ◽  
Weight Bearing ◽  
Family Members ◽  
Dominant Negative ◽  
Hindlimb Unloading ◽  
Skeletal Muscle Atrophy ◽  
Significant Advance ◽  
Protein Ubiquitination

Skeletal muscle atrophy is associated with a marked and sustained activation of nuclear factor-κB (NF-κB) activity. Previous work showed that p50 is one of the NF-κB family members required for this activation and for muscle atrophy. In this work, we tested whether another NF-κB family member, c-Rel, is required for atrophy. Because endogenous inhibitory factor κBα (IκBα) was activated (i.e., decreased) at 3 and 7 days of muscle disuse (i.e., hindlimb unloading), we also tested if IκBα, which binds and retains Rel proteins in the cytosol, is required for atrophy and intermediates of the atrophy process. To do this, we electrotransferred a dominant negative IκBα (IκBαΔN) in soleus muscles, which were either unloaded or weight bearing. IκBαΔN expression abolished the unloading-induced increase in both NF-κB activation and total ubiquitinated protein. IκBαΔN inhibited unloading-induced fiber atrophy by 40%. The expression of certain genes known to be upregulated with atrophy were significantly inhibited by IκBαΔN expression during unloading, including MAFbx/atrogin-1, Nedd4, IEX, 4E-BP1, FOXO3a, and cathepsin L, suggesting these genes may be targets of NF-κB transcription factors. In contrast, c-Rel was not required for atrophy because the unloading-induced markers of atrophy were the same in c-rel−/− and wild-type mice. Thus IκBα degradation is required for the unloading-induced decrease in fiber size, the increase in protein ubiquitination, activation of NF-κB signaling, and the expression of specific atrophy genes, but c-Rel is not. These data represent a significant advance in our understanding of the role of NF-κB/IκB family members in skeletal muscle atrophy, and they provide new candidate NF-κB target genes for further study.

scholarly journals NF-κB but not FoxO sites in the MuRF1 promoter are required for transcriptional activation in disuse muscle atrophy

2014 ◽  
Vol 306 (8) ◽  
pp. C762-C767 ◽  
Author(s):  
Chia-Ling Wu ◽  
Evangeline W. Cornwell ◽  
Robert W. Jackman ◽  
Susan C. Kandarian
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Transcriptional Activation ◽  
Weight Bearing ◽  
Gene Activation ◽  
Hindlimb Unloading ◽  
Skeletal Muscle Atrophy ◽  
Luciferase Reporter ◽  
Disuse Atrophy

The muscle-specific ring finger protein 1 (MuRF1) gene is required for most types of skeletal muscle atrophy yet we have little understanding of its transcriptional regulation. The purpose of this study is to identify whether NF-κB and/or FoxO response elements in the MuRF1 promoter are required for MuRF1 gene activation during skeletal muscle atrophy due to the removal of hindlimb weight bearing (“unloading”). Both NF-κB -dependent and FoxO-dependent luciferase reporter activities were significantly increased at 5 days of unloading. Using a 4.4-kb MuRF1 promoter reporter construct, a fourfold increase in reporter (i.e., luciferase) activity was found in rat soleus muscles after 5 days of hindlimb unloading. This activation was abolished by mutagenesis of either of the two distal putative NF-κB sites or all three putative NF-κB sites but not by mutagenesis of all four putative FoxO sites. This work provides the first direct evidence that NF-κB sites, but not FoxO sites, are required for MuRF1 promoter activation in muscle disuse atrophy in vivo.

scholarly journals Osteocytic Connexin43 Channels Regulate Bone–Muscle Crosstalk

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 237
Author(s):  
Guobin Li ◽  
Lan Zhang ◽  
Kaiting Ning ◽  
Baoqiang Yang ◽  
Francisca M. Acosta ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Transgenic Mice ◽  
Muscle Mass ◽  
Muscle Protein ◽  
Contractile Force ◽  
Fast Twitch Muscle ◽  
And Function ◽  
Fast Twitch ◽  
Muscle Contractile

Bone–muscle crosstalk plays an important role in skeletal biomechanical function, the progression of numerous pathological conditions, and the modulation of local and distant cellular environments. Previous work has revealed that the deletion of connexin (Cx) 43 in osteoblasts, and consequently, osteocytes, indirectly compromises skeletal muscle formation and function. However, the respective roles of Cx43-formed gap junction channels (GJs) and hemichannels (HCs) in the bone–muscle crosstalk are poorly understood. To this end, we used two Cx43 osteocyte-specific transgenic mouse models expressing dominant negative mutants, Δ130–136 (GJs and HCs functions are inhibited), and R76W (only GJs function is blocked), to determine the effect of these two types of Cx43 channels on neighboring skeletal muscle. Blockage of osteocyte Cx43 GJs and HCs in Δ130–136 mice decreased fast-twitch muscle mass with reduced muscle protein synthesis and increased muscle protein degradation. Both R76W and Δ130–136 mice exhibited decreased muscle contractile force accompanied by a fast-to-slow fiber transition in typically fast-twitch muscles. In vitro results further showed that myotube formation of C2C12 myoblasts was inhibited after treatment with the primary osteocyte conditioned media (PO CM) from R76W and Δ130–136 mice. Additionally, prostaglandin E2 (PGE2) level was significantly reduced in both the circulation and PO CM of the transgenic mice. Interestingly, the injection of PGE2 to the transgenic mice rescued fast-twitch muscle mass and function; however, this had little effect on protein synthesis and degradation. These findings indicate a channel-specific response: inhibition of osteocytic Cx43 HCs decreases fast-twitch skeletal muscle mass alongside reduced protein synthesis and increased protein degradation. In contrast, blockage of Cx43 GJs results in decreased fast-twitch skeletal muscle contractile force and myogenesis, with PGE2 partially accounting for the measured differences.

Resistance exercise and growth hormone as countermeasures for skeletal muscle atrophy in hindlimb-suspended rats

1994 ◽  
Vol 267 (2) ◽  
pp. R365-R371 ◽  
Author(s):  
J. K. Linderman ◽  
K. L. Gosselink ◽  
F. W. Booth ◽  
V. R. Mukku ◽  
R. E. Grindeland
Keyword(s):  
Skeletal Muscle ◽  
Growth Hormone ◽  
Resistance Exercise ◽  
Protein Content ◽  
Muscle Atrophy ◽  
Myofibrillar Protein ◽  
Hindlimb Suspension ◽  
Skeletal Muscle Atrophy ◽  
Plantar Flexor ◽  
Fast Twitch

Unweighting of rat hindlimb muscles results in skeletal muscle atrophy, decreased protein synthesis, and reduced growth hormone (GH) secretion. Resistance exercise (ladder climbing) and GH treatment partially attenuate skeletal muscle atrophy in hypophysectomized hindlimb-suspended rats. It was hypothesized that a combination of multiple bouts of daily resistance exercise and GH (1 mg.kg-1.day-1) would prevent skeletal muscle atrophy in growing nonhypophysectomized hindlimb-suspended rats. Hindlimb suspension decreased the absolute (mg/pair) and relative (mg/100 g body wt) weights of the soleus, a slow-twitch plantar flexor, by 30 and 21%, respectively, and the absolute and relative weights of the gastrocnemius, a predominantly fast-twitch plantar flexor, by 20 and 11%, respectively (P < 0.05). Exercise did not increase soleus mass but attenuated loss of relative wet weight in the gastrocnemius muscles of hindlimb-suspended rats (P < 0.05). Hindlimb suspension decreased gastrocnemius myofibrillar protein content and synthesis (mg/day) by 26 and 64%, respectively (P < 0.05). The combination of exercise and GH attenuated loss of gastrocnemius myofibrillar protein content and synthesis by 70 and 23%, respectively (P < 0.05). Results of the present investigation indicate that a combination of GH and resistance exercise attenuates atrophy of unweighted fast-twitch skeletal muscles.

Regulation of translation factors during hindlimb unloading and denervation of skeletal muscle in rats

2001 ◽  
Vol 281 (1) ◽  
pp. C179-C187 ◽  
Author(s):  
Troy A. Hornberger ◽  
R. Bridge Hunter ◽  
Susan C. Kandarian ◽  
Karyn A. Esser
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Muscle Atrophy ◽  
Protein Translation ◽  
Hindlimb Unloading ◽  
Initiation Factor ◽  
Skeletal Muscle Atrophy ◽  
Α Subunit ◽  
Translation Factors ◽  
Ribosomal S6 Kinase

In the rat, denervation and hindlimb unloading are two commonly employed models used to study skeletal muscle atrophy. In these models, muscle atrophy is generally produced by a decrease in protein synthesis and an increase in protein degradation. The decrease in protein synthesis has been suggested to occur by an inhibition at the level of protein translation. To better characterize the regulation of protein translation, we investigated the changes that occur in various translation initiation and elongation factors. We demonstrated that both hindlimb unloading and denervation produce alterations in the phosphorylation and/or total amount of the 70-kDa ribosomal S6 kinase, eukaryotic initiation factor 2 α-subunit, and eukaryotic elongation factor 2. Our findings indicate that the regulation of these protein translation factors differs between the models of atrophy studied and between the muscles evaluated (e.g., soleus vs. extensor digitorum longus).

scholarly journals Protective Effect of Pyropia yezoensis Peptide on Dexamethasone-Induced Myotube Atrophy in C2C12 Myotubes

Marine Drugs ◽  
2019 ◽  
Vol 17 (5) ◽  
pp. 284 ◽  
Author(s):  
Min-Kyeong Lee ◽  
Jeong-Wook Choi ◽  
Youn Hee Choi ◽  
Taek-Jeong Nam
Keyword(s):  
Skeletal Muscle ◽  
Growth Factor ◽  
Signaling Pathway ◽  
Muscle Atrophy ◽  
Skeletal Muscle Atrophy ◽  
C2c12 Myotubes ◽  
Protective Effects ◽  
Factor I ◽  
Igf I ◽  
Foxo Signaling Pathway

Dexamethasone (DEX), a synthetic glucocorticoid, causes skeletal muscle atrophy. This study examined the protective effects of Pyropia yezoensis peptide (PYP15) against DEX-induced myotube atrophy and its association with insulin-like growth factor-I (IGF-I) and the Akt/mammalian target of rapamycin (mTOR)-forkhead box O (FoxO) signaling pathway. To elucidate the molecular mechanisms underlying the effects of PYP15 on DEX-induced myotube atrophy, C2C12 myotubes were treated for 24 h with 100 μM DEX in the presence or absence of 500 ng/mL PYP15. Cell viability assays revealed no PYP15 toxicity in C2C12 myotubes. PYP15 activated the insulin-like growth factor-I receptor (IGF-IR) and Akt-mTORC1 signaling pathway in DEX-induced myotube atrophy. In addition, PYP15 markedly downregulated the nuclear translocation of transcription factors FoxO1 and FoxO3a, and inhibited 20S proteasome activity. Furthermore, PYP15 inhibited the autophagy-lysosomal pathway in DEX-stimulated myotube atrophy. Our findings suggest that PYP15 treatment protected against myotube atrophy by regulating IGF-I and the Akt-mTORC1-FoxO signaling pathway in skeletal muscle. Therefore, PYP15 treatment appears to exert protective effects against skeletal 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.

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