Atrophy responses to muscle inactivity. II. Molecular markers of protein deficits

2003 ◽  
Vol 95 (2) ◽  
pp. 791-802 ◽  
Author(s):  
F. Haddad ◽  
R. R. Roy ◽  
H. Zhong ◽  
V. R. Edgerton ◽  
K. M. Baldwin
Keyword(s):  
Spinal Cord ◽  
Molecular Markers ◽  
Protein Degradation ◽  
Muscle Atrophy ◽  
Binding Protein ◽  
Skeletal Muscle Atrophy ◽  
Hindlimb Muscles ◽  
Complete Transection ◽  
Igf I ◽  
Muscle Inactivity

We examined the expression of several molecular markers of protein balance in response to skeletal muscle atrophy induced by spinal cord isolation (SI; i.e., a complete transection of the spinal cord at both a midthoracic and a high sacral level plus complete deafferentation between the two transection sites). This treatment nearly eliminates neuromuscular activity (activation and loading) of the hindlimb muscles while maintaining neuromuscular connectivity. SI was associated with a reduced transcriptional activity (via pre-mRNA analyses) of myosin heavy chain (MHC) and actin. In addition, there was an increased gene expression of enzyme systems impacting protein degradation (calpain-1; plus enzymes associated with polyubquitination processes) that could further contribute to the protein deficits in the SI muscles via degradative pathways. IGF-I receptor and binding protein-5 mRNA expression was induced throughout the 15-day period of SI, whereas IGF-I mRNA was induced at 8 and 15 days. These responses occurred in the absence of an upregulation of translational regulatory proteins (p70 S6 kinase; eukaryotic 4E binding protein 1) to compensate for the decreased protein translational capacity. These data collectively demonstrate that 1) the molecular changes accompanying SI-induced muscle atrophy are not necessarily the reverse of those occurring during muscle hypertrophy, and 2) the rapid and marked atrophy that defines this model of muscle inactivity is likely the result of multifactorial processes affecting transcription, translation, and protein degradation.

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.

scholarly journals Muscle Reinnervation with Delayed or Immediate Transplant of Embryonic Ventral Spinal Cord Cells into Adult Rat Peripheral Nerve

2002 ◽  
Vol 11 (3) ◽  
pp. 241-250 ◽  
Author(s):  
Robert M. Grumbles ◽  
Patrick Wood ◽  
Michelle Rudinsky ◽  
Anna M. Gomez ◽  
Christine K. Thomas
Keyword(s):  
Spinal Cord ◽  
Peripheral Nerve ◽  
Cell Transplantation ◽  
Muscle Atrophy ◽  
Skeletal Muscle Atrophy ◽  
Nerve Degeneration ◽  
Adult Rat ◽  
Muscle Reinnervation ◽  
The Mean ◽  
Ventral Spinal Cord

Muscle denervation is common in various neuromuscular diseases and after trauma. It induces skeletal muscle atrophy. Only muscle reinnervation leads to functional recovery. In previous studies, denervated adult rat muscles were rescued by transplantation of embryonic day 14–15 (E14–15) ventral spinal cord cells into a nearby peripheral nerve. In the present study, changes were made in the environment into which the cells were placed to test whether reinnervation was improved by: 1) prior nerve degeneration, induced by sciatic nerve transection 1 week before cell transplantation; 2) transplantation of 1 million versus 5 million cells; 3) addition of nerve growth factor (NGF) to the transplant. Ten weeks after cell transplantation, axons had grown from all of the transplants. The numbers of myelinated axons that regenerated into the tibial, medial (MG), and lateral gastrocnemius-soleus (LGS) nerves were similar across treatments. The mean diameters of large LGS axons (>6 μm) were significantly larger with nerve degeneration before transplantation. The mean diameters of MG and LGS axons were significantly larger with transplantation of 1 million versus 5 million cells. Silver-stained experimental and control lateral gastronemius (LG) muscles showed axons that terminated at motor end plates. Nodal and terminal sprouts were more common in reinnervated muscles (45–63% of all end plates) than in control muscles (10%). Electrical stimulation of the transplants induced weak contractions in 39 of 47 MG muscles (83%) and 33 of 46 LG muscles (72%) but at higher voltages than needed to excite control muscles. The threshold for MG contraction was lower with transplantation of 1 million cells, while LG thresholds were lower without NGF. The cross-sectional area of whole LG muscles was significantly larger with cell transplantation (immediate or delayed) than with media alone, but all of these muscle areas were reduced significantly compared with control muscle areas. These data suggest that delayed transplantation of fewer cells without NGF assists regeneration of larger diameter axons and prevents some muscle atrophy.

Ectopic expression of IGF‐I and Shh by skeletal muscle inhibits disuse‐mediated skeletal muscle atrophy and bone osteopenia in vivo

2003 ◽  
Vol 18 (1) ◽  
pp. 221-223 ◽  
Author(s):  
Mohammed Borhan Alzghoul ◽  
Dave Gerrard ◽  
Bruce A. Watkins ◽  
Kevin Hannon
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Ectopic Expression ◽  
Skeletal Muscle Atrophy ◽  
Igf I

scholarly journals Protein translation, proteolysis and autophagy in human skeletal muscle atrophy after spinal cord injury

2018 ◽  
Vol 223 (3) ◽  
pp. e13051 ◽  
Author(s):  
L. S. Lundell ◽  
M. Savikj ◽  
E. Kostovski ◽  
P. O. Iversen ◽  
J. R. Zierath ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Muscle Atrophy ◽  
Human Skeletal Muscle ◽  
Protein Translation ◽  
Skeletal Muscle Atrophy ◽  
Cord Injury

scholarly journals Intraspinal Grafting of Serotonergic Neurons Modifies Expression of Genes Important for Functional Recovery in Paraplegic Rats

2018 ◽  
Vol 2018 ◽  
pp. 1-15 ◽  
Author(s):  
Krzysztof Miazga ◽  
Hanna Fabczak ◽  
Ewa Joachimiak ◽  
Małgorzata Zawadzka ◽  
Łucja Krzemień-Ojak ◽  
...  
Keyword(s):  
Gene Expression ◽  
Spinal Cord ◽  
Functional Recovery ◽  
Serotonergic Neurons ◽  
Locomotor Recovery ◽  
Thoracic Level ◽  
Hindlimb Muscles ◽  
Complete Transection ◽  
Expression Of Genes ◽  
Influence Functional

Serotonin (5-hydroxytryptamine; 5-HT) plays an important role in control of locomotion, partly through direct effects on motoneurons. Spinal cord complete transection (SCI) results in changes in 5-HT receptors on motoneurons that influence functional recovery. Activation of 5-HT2A and 5-HT7 receptors improves locomotor hindlimb movements in paraplegic rats. Here, we analyzed the mRNA of 5-HT2A and 5-HT7 receptors (encoded by Htr2a and Htr7 genes, resp.) in motoneurons innervating tibialis anterior (TA) and gastrocnemius lateralis (GM) hindlimb muscles and the tail extensor caudae medialis (ECM) muscle in intact as well as spinal rats. Moreover, the effect of intraspinal grafting of serotonergic neurons on Htr2a and Htr7 gene expression was examined to test the possibility that the graft origin 5-HT innervation in the spinal cord of paraplegic rats could reverse changes in gene expression induced by SCI. Our results indicate that SCI at the thoracic level leads to changes in Htr2a and Htr7 gene expression, whereas transplantation of embryonic serotonergic neurons modifies these changes in motoneurons innervating hindlimb muscles but not those innervating tail muscles. This suggests that the upregulation of genes critical for locomotor recovery, resulting in limb motoneuron plasticity, might account for the improved locomotion in grafted animals.

IGF-I stimulates muscle growth by suppressing protein breakdown and expression of atrophy-related ubiquitin ligases, atrogin-1 and MuRF1

2004 ◽  
Vol 287 (4) ◽  
pp. E591-E601 ◽  
Author(s):  
Jennifer M. Sacheck ◽  
Akira Ohtsuka ◽  
S. Christine McLary ◽  
Alfred L. Goldberg
Keyword(s):  
Protein Degradation ◽  
Muscle Atrophy ◽  
Muscle Growth ◽  
Ring Finger ◽  
Ubiquitin Ligases ◽  
Growth Stimulation ◽  
Akt Pathway ◽  
Myofibrillar Proteins ◽  
Igf I ◽  
Mrna Content

Muscle atrophy results primarily from accelerated protein degradation and is associated with increased expression of two muscle-specific ubiquitin ligases (E3s): atrogin-1 and muscle ring finger 1 (MuRF1). Glucocorticoids are essential for many types of muscle atrophy, and their effects are opposite to those of insulin-like growth factor I (IGF-I) and insulin, which promote growth. In myotubes, dexamethasone (Dex) inhibited growth and enhanced breakdown of long-lived cell proteins, especially myofibrillar proteins (as measured by 3-methylhistidine release), while also increasing atrogin-1 and MuRF1 mRNA. Conversely, IGF-I suppressed protein degradation and prevented the Dex-induced increase in proteolysis. IGF-I rapidly reduced atrogin-1 expression within 1 h by blocking mRNA synthesis without affecting mRNA degradation, whereas IGF-I decreased MuRF1 mRNA slowly. IGF-I and insulin also blocked Dex induction of these E3s and several other atrophy-related genes (“atrogenes”). Changes in overall proteolysis with Dex and IGF-I correlated tightly with changes in atrogin-1 mRNA content, but not with changes in MuRF1 mRNA. IGF-I activates the phosphatidylinositol 3-kinase (PI3K)-Akt pathway, and inhibition of this pathway [but not the calcineurin-nuclear factor of activated T cell (NFAT) or the MEK-ERK pathway] increased proteolysis and atrogin-1 mRNA expression. Thus an important component of growth stimulation by IGF-I, through the PI3K-Akt pathway, is its ability to rapidly suppress transcription of the atrophy-related E3 atrogin-1 and other atrogenes and degradation of myofibrillar proteins.

Inhibition of glycogen synthase kinase-3β activity is sufficient to stimulate myogenic differentiation

2006 ◽  
Vol 290 (2) ◽  
pp. C453-C462 ◽  
Author(s):  
Jos L. J. van der Velden ◽  
Ramon C. J. Langen ◽  
Marco C. J. M. Kelders ◽  
Emiel F. M. Wouters ◽  
Yvonne M. W. Janssen-Heininger ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Glycogen Synthase ◽  
Muscle Growth ◽  
Glycogen Synthase Kinase ◽  
Skeletal Muscle Atrophy ◽  
Glycogen Synthase Kinase 3Β ◽  
Igf I ◽  
Gsk 3Β ◽  
Stimulation Of

Skeletal muscle atrophy is a prominent and disabling feature of chronic wasting diseases. Prevention or reversal of muscle atrophy by administration of skeletal muscle growth (hypertrophy)-stimulating agents such as insulin-like growth factor I (IGF-I) could be an important therapeutic strategy in these diseases. To elucidate the IGF-I signal transduction responsible for muscle formation (myogenesis) during muscle growth and regeneration, we applied IGF-I to differentiating C2C12 myoblasts and evaluated the effects on phosphatidylinositol 3-kinase (PI3K)/Akt/glycogen synthase kinase-3β (GSK-3β) signaling and myogenesis. IGF-I caused phosphorylation and inactivation of GSK-3β activity via signaling through the PI3K/Akt pathway. We assessed whether pharmacological inhibition of GSK-3β with lithium chloride (LiCl) was sufficient to stimulate myogenesis. Addition of IGF-I or LiCl stimulated myogenesis, evidenced by increased myotube formation, muscle creatine kinase (MCK) activity, and troponin I (TnI) promoter transactivation during differentiation. Moreover, mRNAs encoding MyoD, Myf-5, myogenin, TnI-slow, TnI-fast, MCK, and myoglobin were upregulated in myoblasts differentiated in the presence of IGF-I or LiCl. Importantly, blockade of GSK-3β inhibition abrogated IGF-I- but not LiCl-dependent stimulation of myogenic mRNA accumulation, suggesting that the promyogenic effects of IGF-I require GSK-3β inactivation and revealing an important negative regulatory role for GSK-3β in myogenesis. Therefore, this study identifies GSK-3β as a potential target for pharmacological stimulation of muscle growth.

scholarly journals Perlecan Facilitates Neuronal Nitric Oxide Synthase Delocalization in Denervation-Induced Muscle Atrophy

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2524 ◽  
Author(s):  
Satoshi Nakada ◽  
Yuri Yamashita ◽  
Shuichi Machida ◽  
Yuko Miyagoe-Suzuki ◽  
Eri Arikawa-Hirasawa
Keyword(s):  
Nitric Oxide ◽  
Skeletal Muscle ◽  
Nitric Oxide Synthase ◽  
Protein Degradation ◽  
Muscle Atrophy ◽  
Neuronal Nitric Oxide Synthase ◽  
Skeletal Muscle Atrophy ◽  
Extracellular Matrix Molecule ◽  
Stress Dependent ◽  
Oxide Synthase

Perlecan is an extracellular matrix molecule anchored to the sarcolemma by a dystrophin–glycoprotein complex. Perlecan-deficient mice are tolerant to muscle atrophy, suggesting that perlecan negatively regulates mechanical stress-dependent skeletal muscle mass. Delocalization of neuronal nitric oxide synthase (nNOS) from the sarcolemma to the cytosol triggers protein degradation, thereby initiating skeletal muscle atrophy. We hypothesized that perlecan regulates nNOS delocalization and activates protein degradation during this process. To determine the role of perlecan in nNOS-mediated mechanotransduction, we used sciatic nerve transection as a denervation model of gastrocnemius muscles. Gastrocnemius muscle atrophy was significantly lower in perinatal lethality-rescued perlecan-knockout (Hspg2−/−-Tg) mice than controls (WT-Tg) on days 4 and 14 following surgery. Immunofluorescence microscopy showed that cell membrane nNOS expression was reduced by denervation in WT-Tg mice, with marginal effects in Hspg2−/−-Tg mice. Moreover, levels of atrophy-related proteins—i.e., FoxO1a, FoxO3a, atrogin-1, and Lys48-polyubiquitinated proteins—increased in the denervated muscles of WT-Tg mice but not in Hspg2−/−-Tg mice. These findings suggest that during denervation, perlecan promotes nNOS delocalization from the membrane and stimulates protein degradation and muscle atrophy by activating FoxO signaling and the ubiquitin–proteasome system.

scholarly journals Proteomic and bioinformatic analyses of spinal cord injury-induced skeletal muscle atrophy in rats

2016 ◽  
Vol 14 (1) ◽  
pp. 165-174 ◽  
Author(s):  
ZHI-JIAN WEI ◽  
XIAN-HU ZHOU ◽  
BAO-YOU FAN ◽  
WEI LIN ◽  
YI-MING REN ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Muscle Atrophy ◽  
Skeletal Muscle Atrophy ◽  
Cord Injury
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