Skeletal muscle calcineurin: influence of phenotype adaptation and atrophy

2001 ◽  
Vol 280 (4) ◽  
pp. R1256-R1260 ◽  
Author(s):  
Espen E. Spangenburg ◽  
Jay H. Williams ◽  
Roland R. Roy ◽  
Robert J. Talmadge
Keyword(s):  
Skeletal Muscle ◽  
Muscle Mass ◽  
Contractile Activity ◽  
Muscle Growth ◽  
Type I ◽  
Vastus Intermedius ◽  
Slow Fiber ◽  
Highly Correlated ◽  
Molecular Signals ◽  
And Control

Calcineurin (CaN) has been implicated as a signaling molecule that can transduce physiological stimuli (e.g., contractile activity) into molecular signals that initiate slow-fiber phenotypic gene expression and muscle growth. To determine the influence of muscle phenotype and atrophy on CaN levels in muscle, the levels of soluble CaN in rat muscles of varying phenotype, as assessed by myosin heavy chain (MHC)-isoform proportions, were determined by Western blotting. CaN levels were significantly greater in the plantaris muscle containing predominantly fast (IIx and IIb) MHC isoforms, compared with the soleus (predominantly type I MHC) or vastus intermedius (VI, contains all 4 adult MHC isoforms). Three months after a complete spinal cord transection (ST), the CaN levels in the VI muscle were significantly reduced, despite a significant increase in fast MHC isoforms. Surprisingly, the levels of CaN in the VI were highly correlated with muscle mass but not MHC isoform proportions in ST and control rats. These data demonstrate that CaN levels in skeletal muscle are highly correlated to muscle mass and that the normal relationship with phenotype is lost after ST.

The Effects of Aging and Training on Skeletal Muscle

1998 ◽  
Vol 26 (4) ◽  
pp. 598-602 ◽  
Author(s):  
Donald T. Kirkendall ◽  
William E. Garrett
Keyword(s):  
Skeletal Muscle ◽  
Muscle Mass ◽  
Muscle Function ◽  
Cellular Level ◽  
Type I ◽  
Loss Of Function ◽  
Skeletal Muscle Function ◽  
Cross Sectional ◽  
Age Related ◽  
General Slowing

Aging results in a gradual loss of muscle function, and there are predictable age-related alterations in skeletal muscle function. The typical adult will lose muscle mass with age; the loss varies according to sex and the level of muscle activity. At the cellular level, muscles loose both cross-sectional area and fiber numbers, with type II muscle fibers being the most affected by aging. Some denervation of fibers may occur. The combination of these factors leads to an increased percentage of type I fibers in older adults. Metabolically, the glycolytic enzymes seem to be little affected by aging, but the aerobic enzymes appear to decline with age. Aged skeletal muscle produces less force and there is a general “slowing” of the mechanical characteristics of muscle. However, neither reduced muscle demand nor the subsequent loss of function is inevitable with aging. These losses can be minimized or even reversed with training. Endurance training can improve the aerobic capacity of muscle, and resistance training can improve central nervous system recruitment of muscle and increase muscle mass. Therefore, physical activity throughout life is encouraged to prevent much of the age-related impact on skeletal muscle.

scholarly journals Hyaluronic acid, HAS1, and HAS2 are significantly upregulated during muscle hypertrophy

2012 ◽  
Vol 303 (5) ◽  
pp. C577-C588 ◽  
Author(s):  
Sarah Calve ◽  
Jahdonna Isaac ◽  
Jonathan P. Gumucio ◽  
Christopher L. Mendias
Keyword(s):  
Skeletal Muscle ◽  
Hyaluronic Acid ◽  
Type I Collagen ◽  
Muscle Growth ◽  
Type I ◽  
Muscle Adaptation ◽  
Cell Recruitment ◽  
Regeneration In Vitro ◽  
Muscle Progenitor Cell

Hyaluronic acid (HA) is a component of the extracellular matrix (ECM) in most vertebrate tissues and is thought to play a significant role during development, wound healing, and regeneration. In vitro studies have shown that HA enhances muscle progenitor cell recruitment and inhibits premature myotube fusion, implicating a role for this glycosaminoglycan in functional repair. However, the spatiotemporal distribution of HA during muscle growth and repair was unknown. We hypothesized that inducing hypertrophy via synergist ablation would increase the expression of HA and the HA synthases (HAS1–HAS3). We found that HA and HAS1–HAS3 were significantly upregulated within the plantaris muscle in response to Achilles tenectomy. HA concentration significantly increased 2.8-fold after 2 days but decreased towards levels comparable to age-matched controls by 14 days. Using immunohistochemistry, we found the colocalization of HAS1–HAS3 with macrophages, blood vessel epithelia, and fibroblasts varied in response to time and/or tenectomy. At the level of gene expression, only HAS1 and HAS2 significantly increased with respect to both time and tenectomy. The profiles of additional genes that influence ECM composition during muscle repair, tenascin-C, type I collagen, the HA-degrading hyaluronidases (Hyal) and matrix metalloproteinases (MMP) were also investigated. Hyal1 and Hyal2 were highly expressed in skeletal muscle but did not change after tenectomy; however, indicators of hypertrophy, MMP-2 and MMP-14, were significantly upregulated from 2 to 14 days. These results indicate that HA levels dynamically change in response to a hypertrophic stimulus and various cells may participate in this mechanism of skeletal muscle adaptation.

scholarly journals Total and Free Deoxypyridinoline after Acute Osteoclast Activity Inhibition

1999 ◽  
Vol 45 (9) ◽  
pp. 1510-1516 ◽  
Author(s):  
Alessandro Rubinacci ◽  
Raffaella Melzi ◽  
Maria Zampino ◽  
Armando Soldarini ◽  
Isabella Villa
Keyword(s):  
Type I Collagen ◽  
Degradation Process ◽  
Type I ◽  
Short Term ◽  
Oral Calcium ◽  
Osteoclast Activity ◽  
High Bone ◽  
Highly Correlated ◽  
Acute Changes ◽  
And Control

Abstract Background: Deoxypyridinoline (Dpd) is one of the two pyridinium cross-links that provide structural rigidity to type I collagen in bone. During osteoclastic resorption, Dpd is released into circulation and is excreted in the urine in free and peptide-bound forms. Free and total Dpd are highly correlated, but whether the free-to-total cross-link ratio is constant in both normal and high bone turnover states remains controversial. To compare free and total Dpd performance in a physiological condition, urinary free and total Dpd were measured after a short-term inhibition of osteoclast activity such as that induced by an oral calcium load. Methods: Total and free Dpd were measured by HPLC and by immunosorbent assay, respectively, in two groups of subjects, one (calcium-treated; n = 16) taking calcium and the other not (control; n = 9). Results: The urinary excretion of total Dpd at 2 and 4 h after oral calcium loading was decreased compared with controls. By contrast, changes in free Dpd were similar in the calcium-treated and control groups, reflecting only circadian rhythm. Conclusions: Total and free Dpd do not show comparable sensitivity in detecting short-term inhibition of osteoclast activity. The degradation process of peptide-bound to free Dpd could render free Dpd insensitive to acute changes of osteoclast activity.

scholarly journals Functional redundancy of type I and type II receptors in the regulation of skeletal muscle growth by myostatin and activin A

2020 ◽  
Vol 117 (49) ◽  
pp. 30907-30917 ◽  
Author(s):  
Se-Jin Lee ◽  
Adam Lehar ◽  
Yewei Liu ◽  
Chi Hai Ly ◽  
Quynh-Mai Pham ◽  
...  
Keyword(s):  
Family Member ◽  
Muscle Mass ◽  
Transforming Growth Factor ◽  
Muscle Growth ◽  
Functional Redundancy ◽  
Activin A ◽  
Metabolic Effects ◽  
Type I ◽  
Type Ii

Myostatin (MSTN) is a transforming growth factor-β (TGF-β) family member that normally acts to limit muscle growth. The function of MSTN is partially redundant with that of another TGF-β family member, activin A. MSTN and activin A are capable of signaling through a complex of type II and type I receptors. Here, we investigated the roles of two type II receptors (ACVR2 and ACVR2B) and two type I receptors (ALK4 and ALK5) in the regulation of muscle mass by these ligands by genetically targeting these receptors either alone or in combination specifically in myofibers in mice. We show that targeting signaling in myofibers is sufficient to cause significant increases in muscle mass, showing that myofibers are the direct target for signaling by these ligands in the regulation of muscle growth. Moreover, we show that there is functional redundancy between the two type II receptors as well as between the two type I receptors and that all four type II/type I receptor combinations are utilized in vivo. Targeting signaling specifically in myofibers also led to reductions in overall body fat content and improved glucose metabolism in mice fed either regular chow or a high-fat diet, demonstrating that these metabolic effects are the result of enhanced muscling. We observed no effect, however, on either bone density or muscle regeneration in mice in which signaling was targeted in myofibers. The latter finding implies that MSTN likely signals to other cells, such as satellite cells, in addition to myofibers to regulate muscle homeostasis.

scholarly journals The bone morphogenetic protein axis is a positive regulator of skeletal muscle mass

2013 ◽  
Vol 203 (2) ◽  
pp. 345-357 ◽  
Author(s):  
Catherine E. Winbanks ◽  
Justin L. Chen ◽  
Hongwei Qian ◽  
Yingying Liu ◽  
Bianca C. Bernardo ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Bone Morphogenetic Protein ◽  
Signaling Pathway ◽  
Muscle Mass ◽  
Muscle Wasting ◽  
Muscle Growth ◽  
Bmp Signaling ◽  
Positive Regulator ◽  
Bmp Receptors ◽  
Morphogenetic Protein

Although the canonical transforming growth factor β signaling pathway represses skeletal muscle growth and promotes muscle wasting, a role in muscle for the parallel bone morphogenetic protein (BMP) signaling pathway has not been defined. We report, for the first time, that the BMP pathway is a positive regulator of muscle mass. Increasing the expression of BMP7 or the activity of BMP receptors in muscles induced hypertrophy that was dependent on Smad1/5-mediated activation of mTOR signaling. In agreement, we observed that BMP signaling is augmented in models of muscle growth. Importantly, stimulation of BMP signaling is essential for conservation of muscle mass after disruption of the neuromuscular junction. Inhibiting the phosphorylation of Smad1/5 exacerbated denervation-induced muscle atrophy via an HDAC4-myogenin–dependent process, whereas increased BMP–Smad1/5 activity protected muscles from denervation-induced wasting. Our studies highlight a novel role for the BMP signaling pathway in promoting muscle growth and inhibiting muscle wasting, which may have significant implications for the development of therapeutics for neuromuscular disorders.

scholarly journals Myosin heavy chain expression in rodent skeletal muscle: effects of exposure to zero gravity

1993 ◽  
Vol 75 (6) ◽  
pp. 2471-2477 ◽  
Author(s):  
F. Haddad ◽  
R. E. Herrick ◽  
G. R. Adams ◽  
K. M. Baldwin
Keyword(s):  
Skeletal Muscle ◽  
Muscle Protein ◽  
Vastus Lateralis ◽  
Mrna Level ◽  
Relative Content ◽  
Type I ◽  
Zero Gravity ◽  
Mrna Levels ◽  
Heavy Chains ◽  
Vastus Intermedius

This study ascertained the effects of 9 days of zero gravity on the relative (percentage of total) and calculated absolute (mg/muscle) content of isomyosin expressed in both antigravity and locomotor skeletal muscle of ground control (CON) and flight-exposed (FL) rats. Results showed that although there were no differences in body weight between FL and CON animals, a significant reduction in muscle mass occurred in the vastus intermedius (VI) (P < 0.05) but not in the vastus lateralis (VL) or the tibialis anterior. Both total muscle protein and myofibril protein content were not different between the muscle regions examined in the FL and CON groups. In the VI, there were trends for reductions in the relative content of type I and IIa myosin heavy chains (MHCs) that were offset by increases in the relative content of both type IIb and possibly type IIx MHC protein (P > 0.05). mRNA levels were consistent with this pattern (P < 0.05). The same pattern held true for the red region of the VL as examined at both the protein and mRNA level (P < 0.05). When the atrophy process was examined, there were net reductions in the absolute content of both type I and IIa MHCs that were offset by calculated increases in type IIb MHC in both VI and red VL. Collectively, these findings suggest that there are both absolute and relative changes occurring in MHC expression in the "red" regions of antigravity skeletal muscle during exposure to zero gravity that could affect muscle function.

Denervation-induced mitochondrial dysfunction and autophagy in skeletal muscle of apoptosis-deficient animals

2012 ◽  
Vol 303 (4) ◽  
pp. C447-C454 ◽  
Author(s):  
Michael F. N. O′Leary ◽  
Anna Vainshtein ◽  
Heather N. Carter ◽  
Yuan Zhang ◽  
David A. Hood
Keyword(s):  
Skeletal Muscle ◽  
Signaling Pathways ◽  
Muscle Mass ◽  
Contractile Activity ◽  
Double Knockout ◽  
Muscle Disuse ◽  
Subsarcolemmal Mitochondria ◽  
And Function ◽  
Species Production ◽  
Potential Signal

Skeletal muscle undergoes remarkable adaptations in response to chronic decreases in contractile activity, such as a loss of muscle mass, decreases in both mitochondrial content and function, as well as the activation of apoptosis. Although these adaptations are well known, questions remain regarding the signaling pathways that mediated these changes. Autophagy is an organelle turnover pathway that could contribute to these adaptations. The purpose of this study was to determine whether denervation-induced muscle disuse would result in the activation of autophagy gene expression in both wild-type (WT) and Bax/Bak double knockout (DKO) animals, which display an attenuated apoptotic response. Denervation caused a reduction in muscle mass for WT and DKO animals; however, there was a 40% attenuation in muscle atrophy in DKO animals. Mitochondrial state 3 respiration was significantly reduced, and reactive oxygen species production was increased by two- to threefold in both WT and DKO animals. Apoptotic markers, including cytosolic AIF and DNA fragmentation, were elevated in WT, but not in DKO animals following denervation. Autophagy proteins including LC3II, ULK1, ATG7, p62, and Beclin1 were increased similarly following denervation for both WT and DKO. Interestingly, denervation markedly increased the localization of LC3II to subsarcolemmal mitochondria, and this was more pronounced in the DKO animals. Thus denervation-induced muscle disuse activates both apoptotic and autophagic signaling pathways in muscle, and autophagic protein expression does not exhibit a compensatory increase in the presence of attenuated apoptosis. However, the absence of Bax and Bak may represent a potential signal to trigger mitophagy in muscle.

Skeletal muscle myostatin mRNA expression is fiber-type specific and increases during hindlimb unloading

1999 ◽  
Vol 277 (2) ◽  
pp. R601-R606 ◽  
Author(s):  
Christian J. Carlson ◽  
Frank W. Booth ◽  
Scott E. Gordon
Keyword(s):  
Skeletal Muscle ◽  
Muscle Mass ◽  
Soleus Muscle ◽  
Fiber Type ◽  
Weight Bearing ◽  
Mrna Abundance ◽  
Hindlimb Unloading ◽  
Negative Regulator ◽  
Type I ◽  
Mrna Levels

Transgenic mice lacking a functional myostatin (MSTN) gene demonstrate greater skeletal muscle mass resulting from muscle fiber hypertrophy and hyperplasia (McPherron, A. C., A. M. Lawler, and S.-J. Lee. Nature 387: 83–90, 1997). Therefore, we hypothesized that, in normal mice, MSTN may act as a negative regulator of muscle mass. Specifically, we hypothesized that the predominately slow (type I) soleus muscle, which demonstrates greater atrophy than the fast (type II) gastrocnemius-plantaris complex (Gast/PLT), would show more elevation in MSTN mRNA abundance during hindlimb unloading (HU). Surprisingly, MSTN mRNA was not detectable in weight-bearing or HU soleus muscle, which atrophied 42% by the 7th day of HU in female ICR mice. In contrast, MSTN mRNA was present in weight-bearing Gast/PLT muscle and was significantly elevated (67%) at 1 day but not at 3 or 7 days of HU. However, the Gast/PLT muscle had only atrophied 17% by the 7th day of HU. Because the soleus is composed only of type I and IIa fibers, whereas the Gast/PLT expresses type IId/x and IIb in addition to type I and IIa, it was necessary to perform a more careful analysis of the relationship between MSTN mRNA levels and myosin heavy-chain (MHC) isoform expression (as a marker of fiber type). A significant correlation ( r = 0.725, P < 0.0005) was noted between the percentage of MHC isoform IIb expression and MSTN mRNA abundance in several muscles of the mouse hindlimb. These results indicate that MSTN expression is not strongly associated with muscle atrophy induced by HU; however, it is strongly associated with MHC isoform IIb expression in normal muscle.

scholarly journals SHP-2 activates signaling of the nuclear factor of activated T cells to promote skeletal muscle growth

2006 ◽  
Vol 175 (1) ◽  
pp. 87-97 ◽  
Author(s):  
Mara Fornaro ◽  
Peter M. Burch ◽  
Wentian Yang ◽  
Lei Zhang ◽  
Claire E. Hamilton ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
T Cells ◽  
Intracellular Signaling ◽  
Tyrosine Phosphatase ◽  
Muscle Growth ◽  
Interleukin 4 ◽  
Type I ◽  
Nuclear Factor ◽  
Activated T Cells ◽  
Skeletal Muscle Growth

The formation of multinucleated myofibers is essential for the growth of skeletal muscle. The nuclear factor of activated T cells (NFAT) promotes skeletal muscle growth. How NFAT responds to changes in extracellular cues to regulate skeletal muscle growth remains to be fully defined. In this study, we demonstrate that mice containing a skeletal muscle–specific deletion of the tyrosine phosphatase SHP-2 (muscle creatine kinase [MCK]–SHP-2 null) exhibited a reduction in both myofiber size and type I slow myofiber number. We found that interleukin-4, an NFAT-regulated cytokine known to stimulate myofiber growth, was reduced in its expression in skeletal muscles of MCK–SHP-2–null mice. When SHP-2 was deleted during the differentiation of primary myoblasts, NFAT transcriptional activity and myotube multinucleation were impaired. Finally, SHP-2 coupled myotube multinucleation to an integrin-dependent pathway and activated NFAT by stimulating c-Src. Thus, SHP-2 transduces extracellular matrix stimuli to intracellular signaling pathways to promote skeletal muscle growth.

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