Invited Review: Effects of different activity and inactivity paradigms on myosin heavy chain gene expression in striated muscle

2001 ◽  
Vol 90 (1) ◽  
pp. 345-357 ◽  
Author(s):  
Kenneth M. Baldwin ◽  
Fadia Haddad
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Myosin Heavy Chain ◽  
Heavy Chain ◽  
Motor Proteins ◽  
Weight Bearing ◽  
Activity Level ◽  
Type I ◽  
Mechanical Stimuli ◽  
Energy Deprivation

The goal of this mini-review is to summarize findings concerning the role that different models of muscular activity and inactivity play in altering gene expression of the myosin heavy chain (MHC) family of motor proteins in mammalian cardiac and skeletal muscle. This was done in the context of examining parallel findings concerning the role that thyroid hormone (T3, 3,5,3′-triiodothyronine) plays in MHC expression. Findings show that both cardiac and skeletal muscles of experimental animals are initially undifferentiated at birth and then undergo a marked level of growth and differentiation in attaining the adult MHC phenotype in a T3/activity level-dependent fashion. Cardiac MHC expression in small mammals is highly sensitive to thyroid deficiency, diabetes, energy deprivation, and hypertension; each of these interventions induces upregulation of the β-MHC isoform, which functions to economize circulatory function in the face of altered energy demand. In skeletal muscle, hyperthyroidism, as well as interventions that unload or reduce the weight-bearing activity of the muscle, causes slow to fast MHC conversions. Fast to slow conversions, however, are seen under hypothyroidism or when the muscles either become chronically overloaded or subjected to intermittent loading as occurs during resistance training and endurance exercise. The regulation of MHC gene expression by T3 or mechanical stimuli appears to be strongly regulated by transcriptional events, based on recent findings on transgenic models and animals transfected with promoter-reporter constructs. However, the mechanisms by which T3 and mechanical stimuli exert their control on transcriptional processes appear to be different. Additional findings show that individual skeletal muscle fibers have the genetic machinery to express simultaneously all of the adult MHCs, e.g., slow type I and fast IIa, IIx, and IIb, in unique combinations under certain experimental conditions. This degree of heterogeneity among the individual fibers would ensure a large functional diversity in performing complex movement patterns. Future studies must now focus on 1) the signaling pathways and the underlying mechanisms governing the transcriptional/translational machinery that control this marked degree of plasticity and 2) the morphological organization and functional implications of the muscle fiber's capacity to express such a diversity of motor proteins.

scholarly journals Sp3 Proteins Negatively Regulate β Myosin Heavy Chain Gene Expression during Skeletal Muscle Inactivity

2004 ◽  
Vol 24 (24) ◽  
pp. 10777-10791 ◽  
Author(s):  
Gretchen Tsika ◽  
Juan Ji ◽  
Richard Tsika
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Myosin Heavy Chain ◽  
Heavy Chain ◽  
Weight Bearing ◽  
C2c12 Myotubes ◽  
Type I ◽  
Adult Skeletal Muscle ◽  
Nuclear Extracts ◽  
Muscle Inactivity

ABSTRACT In adult skeletal muscle, β myosin heavy chain (βMyHC) gene expression is primarily restricted to slow type I fibers; however, its expression is down-regulated in response to muscle inactivity. Little is known about the signaling pathways and transcription factors that mediate this important functional response. This study demonstrates that increased binding of Sp3 to GC-rich elements in theβ MyHC promoter is a critical event in down-regulation ofβ MyHC gene expression under non-weight-bearing conditions. Conversely, binding of Sp3 to these elements decreased while Sp1 binding increased with nuclear extracts from plantaris muscle exposed to mechanical overload, a stimulus that increases βMyHC gene expression. In addition, these experiments revealed the existence of an Sp4-DNA binding complex when using adult skeletal muscle nuclear extract was used but not when nuclear extracts from cultured myotubes were used. Sp3 proteins are competitive inhibitors of Sp1-mediatedβ MyHC reporter gene transactivation in both Drosophila SL-2 and mouse C2C12 myotubes. Sp4 is a weak activator of βMyHC gene expression in SL-2 cells, which lack endogenous Sp1 activity, but does not activate βMyHC gene expression in C2C12 myotubes, which have high levels of Sp1. These results suggest that competitive binding of Sp family proteins regulate βMyHC gene transcription in response to altered neuromuscular activity.

scholarly journals Calcineurin plays a modulatory role in loading-induced regulation of type I myosin heavy chain gene expression in slow skeletal muscle

2009 ◽  
Vol 297 (4) ◽  
pp. R1037-R1048 ◽  
Author(s):  
Clay E. Pandorf ◽  
Weihua H. Jiang ◽  
Anqi X. Qin ◽  
Paul W. Bodell ◽  
Kenneth M. Baldwin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Myosin Heavy Chain ◽  
Heavy Chain ◽  
Fiber Type ◽  
Hindlimb Suspension ◽  
Chain Gene ◽  
Type I ◽  
Thyroid State

The role of calcineurin (Cn) in skeletal muscle fiber-type expression has been a subject of great interest because of reports indicating that it controls the slow muscle phenotype. To delineate the role of Cn in phenotype remodeling, particularly its role in driving expression of the type I myosin heavy chain (MHC) gene, we used a novel strategy whereby a profound transition from fast to slow fiber type is induced and examined in the absence and presence of cyclosporin A (CsA), a Cn inhibitor. To induce the fast-to-slow transition, we first subjected rats to 7 days of hindlimb suspension (HS) + thyroid hormone [triiodothyronine (T3)] to suppress nearly all expression of type I MHC mRNA in the soleus muscle. HS + T3 was then withdrawn, and rats resumed normal ambulation and thyroid state, during which vehicle or CsA (30 mg·kg−1·day−1) was administered for 7 or 14 days. The findings demonstrate that, despite significant inhibition of Cn, pre-mRNA, mRNA, and protein abundance of type I MHC increased markedly during reloading relative to HS + T3 ( P < 0.05). Type I MHC expression was, however, attenuated by CsA compared with vehicle treatment. In addition, type IIa and IIx MHC pre-mRNA, mRNA, and relative protein levels were increased in Cn-treated compared with vehicle-treated rats. These findings indicate that Cn has a modulatory role in MHC transcription, rather than a role as a primary regulator of slow MHC gene expression.

Distribution of myosin heavy chain isoforms in non-weight-bearing rat soleus muscle fibers

1996 ◽  
Vol 81 (6) ◽  
pp. 2540-2546 ◽  
Author(s):  
Robert J. Talmadge ◽  
Roland R. Roy ◽  
V. Reggie Edgerton
Keyword(s):  
Myosin Heavy Chain ◽  
Soleus Muscle ◽  
Heavy Chain ◽  
De Novo ◽  
Weight Bearing ◽  
Muscle Fibers ◽  
Myosin Heavy Chain Isoforms ◽  
Hindlimb Suspension ◽  
Type I ◽  
Rat Soleus Muscle

Talmadge, Robert J., Roland R. Roy, and V. Reggie Edgerton.Distribution of myosin heavy chain isoforms in non-weight-bearing rat soleus muscle fibers. J. Appl. Physiol. 81(6): 2540–2546, 1996.—The effects of 14 days of spaceflight (SF) or hindlimb suspension (HS) (Cosmos 2044) on myosin heavy chain (MHC) isoform content of the rat soleus muscle and single muscle fibers were determined. On the basis of electrophoretic analyses, there was a de novo synthesis of type IIx MHC but no change in either type I or IIa MHC isoform proportions after either SF or HS compared with controls. The percentage of fibers containing only type I MHC decreased by 26 and 23%, and the percentage of fibers with multiple MHCs increased from 6% in controls to 32% in HS and 34% in SF rats. Type IIx MHC was always found in combination with another MHC or combination of MHCs; i.e., no fibers contained type IIx MHC exclusively. These data suggest that the expression of the normal complement of MHC isoforms in the adult rat soleus muscle is dependent, in part, on normal weight bearing and that the absence of weight bearing induces a shift toward type IIx MHC protein expression in the preexisting type I and IIa fibers of the soleus.

Polyadenylated RNA, actin mRNA, and myosin heavy chain mRNA in young and old human skeletal muscle

1996 ◽  
Vol 270 (2) ◽  
pp. E224-E229 ◽  
Author(s):  
S. Welle ◽  
K. Bhatt ◽  
C. Thornton
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Myosin Heavy Chain ◽  
Heavy Chain ◽  
Human Skeletal Muscle ◽  
Synthesis Rate ◽  
Protein Synthesis Rate ◽  
Type I ◽  
Polyadenylated Rna ◽  
Actin Mrna

The myofibrillar protein synthesis rate in old human skeletal muscle is slower than that in young adult muscle. To examine whether this difference in protein synthesis rate is explained by reduced availability of the mRNAs that encode the most abundant myofibrillar proteins, we determined relative hybridization signals from probes for actin mRNA, myosin heavy chain mRNA, and total polyadenylated RNA in vastus lateralis muscle biopsies taken from young (22- to 31-yr-old) and old (61- to 74-yr-old) human subjects. The mean fractional rate of myofibrillar synthesis was 38% slower in the older muscles, as determined by incorporation of a stable isotope tracer. Total actin and myosin heavy chain mRNAs, and polyadenylated RNA, were determined using slot-blot assays. Isoform-specific determinations of alpha-actin mRNA, type I myosin heavy chain mRNA, and type IIa myosin heavy chain mRNA were done with ribonuclease protection assays. Hybridization signals were expressed relative to tissue DNA content. There was no difference between age groups in total polyadenylated RNA or in any of the specific mRNAs. We conclude that the slower myofibrillar synthesis rate in older muscle is not caused by reduced mRNA availability.

scholarly journals Loss of quadriceps muscle oxidative phenotype and decreased endurance in patients with mild-to-moderate COPD

2013 ◽  
Vol 114 (9) ◽  
pp. 1319-1328 ◽  
Author(s):  
Bram van den Borst ◽  
Ilse G. M. Slot ◽  
Valéry A. C. V. Hellwig ◽  
Bettine A. H. Vosse ◽  
Marco C. J. M. Kelders ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Skeletal Muscle ◽  
Fiber Type ◽  
Airflow Obstruction ◽  
Quadriceps Muscle ◽  
Activity Level ◽  
Load Test ◽  
Type I ◽  
Oxidative Phenotype

Being well-established in advanced chronic obstructive pulmonary disease (COPD), skeletal muscle dysfunction and its underlying pathology have been scarcely investigated in patients with mild-to-moderate airflow obstruction. We hypothesized that a loss of oxidative phenotype (oxphen) associated with decreased endurance is present in the skeletal muscle of patients with mild-to-moderate COPD. In quadriceps muscle biopsies from 29 patients with COPD (forced expiratory volume in 1 s [FEV1] 58 ± 16%pred, body mass index [BMI] 26 ± 4 kg/m2) and 15 controls (BMI 25 ± 3 kg/m2) we assessed fiber type distribution, fiber cross-sectional areas (CSA), oxidative and glycolytic gene expression, OXPHOS protein levels, metabolic enzyme activity, and levels of oxidative stress markers. Quadriceps function was assessed by isokinetic dynamometry, body composition by dual-energy X-ray absorptiometry, exercise capacity by an incremental load test, and physical activity level by accelerometry. Compared with controls, patients had comparable fat-free mass index, quadriceps strength, and fiber CSA, but quadriceps endurance was decreased by 29% ( P = 0.002). Patients with COPD had a clear loss of muscle oxphen: a fiber type I-to-II shift, decreased levels of OXPHOS complexes IV and V subunits (47% and 31%, respectively; P < 0.05), a decreased ratio of 3-hydroxyacyl-CoA dehydrogenase/phosphofructokinase (PFK) enzyme activities (38%, P < 0.05), and decreased peroxisome proliferator-activated receptor-γ coactivator-1α (40%; P < 0.001) vs. increased PFK (67%; P < 0.001) gene expression levels. Within the patient group, markers of oxphen were significantly positively correlated with quadriceps endurance and inversely with the increase in plasma lactate relative to work rate during the incremental test. Levels of protein carbonylation, tyrosine nitration, and malondialdehyde protein adducts were comparable between patients and controls. However, among patients, oxidative stress levels were significantly inversely correlated with markers of oxphen and quadriceps endurance. Reduced muscle endurance associated with underlying loss of muscle oxphen is already present in patients with mild-to-moderate COPD without muscle wasting.

Influence of overload on phenotypic remodeling in regenerated skeletal muscle

2001 ◽  
Vol 281 (5) ◽  
pp. C1686-C1694 ◽  
Author(s):  
A. X. Bigard ◽  
J. Zoll ◽  
F. Ribera ◽  
P. Mateo ◽  
H. Sanchez ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Lactate Dehydrogenase ◽  
Sarcoplasmic Reticulum ◽  
Heavy Chain ◽  
Type I ◽  
Similar Extent ◽  
Surgical Ablation ◽  
Control Of Gene Expression ◽  
Mechanical Overload

We studied the effects of 10 wk of functional overload on the expression of myosin heavy chain (MHC), sarcoplasmic reticulum Ca2+-ATPase isoforms (SERCA), and the activity of several metabolic enzymes in sham and regenerated plantaris muscles. Overload was accomplished by bilateral surgical ablation of its synergists 4 wk after right plantaris muscles regenerated after myotoxic infiltration. The overload-induced muscle enlargement was slightly less in regenerated than in sham muscles [28% ( P < 0.005) and 43% ( P < 0.001), respectively]. Overload led to an increase in type I MHC expression ( P < 0.01) to a similar extent in sham and regenerated plantaris, while the expected shift from type IIb to type IIa MHC was less marked in regenerated than in sham plantaris. The overload-induced decrease in the expression of the fast SERCA isoform and in the activity of the M subunit of lactate dehydrogenase occurred to a similar extent in sham and regenerated plantaris [66% ( P < 0.01) and 27% ( P < 0.005), respectively]. In conclusion, the lesser responses of muscle mass and fast MHC composition of regenerated plantaris to mechanical overload suggest an alteration of the transcriptional, translational, and/or posttranslational control of gene expression in regenerated muscle.

scholarly journals The expression of myosin genes in developing skeletal muscle in the mouse embryo.

1990 ◽  
Vol 111 (4) ◽  
pp. 1465-1476 ◽  
Author(s):  
G E Lyons ◽  
M Ontell ◽  
R Cox ◽  
D Sassoon ◽  
M Buckingham
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Myosin Heavy Chain ◽  
Heavy Chain ◽  
Light Chain ◽  
Myosin Light Chain ◽  
Muscle Development ◽  
Minor Component ◽  
Light Chain Gene ◽  
Skeletal Myosin

Using in situ hybridization, we have investigated the temporal sequence of myosin gene expression in the developing skeletal muscle masses of mouse embryos. The probes used were isoform-specific, 35S-labeled antisense cRNAs to the known sarcomeric myosin heavy chain and myosin alkali light chain gene transcripts. Results showed that both cardiac and skeletal myosin heavy chain and myosin light chain mRNAs were first detected between 9 and 10 d post coitum (p.c.) in the myotomes of the most rostral somites. Myosin transcripts appeared in more caudal somites at later stages in a developmental gradient. The earliest myosin heavy chain transcripts detected code for the embryonic skeletal (MHCemb) and beta-cardiac (MHC beta) isoforms. Perinatal myosin heavy chain (MHCpn) transcripts begin to accumulate at 10.5 d p.c., which is much earlier than previously reported. At this stage, MHCemb is the major MHC transcript. By 12.5 d p.c., MHCpn and MHCemb mRNAs are present to an equal extent, and by 15.5 d p.c. the MHCpn transcript is the major MHC mRNA detected. Cardiac MHC beta transcripts are always present as a minor component. In contrast, the cardiac MLC1A mRNA is initially more abundant than that encoding the skeletal MLC1F isoform. By 12.5 d p.c. the two MLC mRNAs are present at similar levels, and by 15.5 d p.c., MLC1F is the predominant MLC transcript detected. Transcripts for the ventricular/slow (MLC1V) and another fast skeletal myosin light chain (MLC3F) are not detected in skeletal muscle before 15 d p.c., which marks the beginning of the fetal stage of muscle development. This is the first stage at which we can detect differences in expression of myosin genes between developing muscle fibers. We conclude that, during the development of the myotome and body wall muscles, different myosin genes follow independent patterns of activation and accumulation. The data presented are the first detailed study of myosin gene expression at these early stages of skeletal muscle development.

scholarly journals Purα and Purβ Collaborate with Sp3 To Negatively Regulate β-Myosin Heavy Chain Gene Expression duringSkeletal Muscle Inactivity

2006 ◽  
Vol 27 (4) ◽  
pp. 1531-1543 ◽  
Author(s):  
Juan Ji ◽  
Gretchen L. Tsika ◽  
Hansjörg Rindt ◽  
Kathy L. Schreiber ◽  
John J. McCarthy ◽  
...  
Keyword(s):  
Gene Expression ◽  
Myosin Heavy Chain ◽  
Reporter Gene ◽  
Heavy Chain ◽  
Weight Bearing ◽  
Ectopic Expression ◽  
Reporter Gene Expression ◽  
Proximal Promoter ◽  
C2c12 Myotubes ◽  
Adult Skeletal Muscle

ABSTRACT Adult skeletal muscle retains the capability of transcriptional reprogramming. This attribute is readily observable in the non-weight-bearing (NWB) soleus muscle, which undergoes a slow-to-fast fiber type transition concurrent with decreased β-myosin heavy chain (βMyHC) gene expression. Our previous work showed that Sp3 contributes to decreased βMyHC gene expression under NWB conditions. In this study, we demonstrate that physical and functional interactions between Sp3, Purα, and Purβ proteins mediate repression of βMyHC expression under NWB conditions. Binding of Purα or Purβ to the single-stranded βMyHC distal negative regulatory element-sense strand (dβNRE-S) element is markedly increased under NWB conditions. Ectopic expression of Purα and Purβ decreasedβ MyHC reporter gene expression, while mutation of the dβNRE-S element increased expression in C2C12 myotubes. The dβNRE-S element conferred Pur-dependent decreased expression on a minimal thymidine kinase promoter. Short interfering RNA sequences specific for Sp3 or for Purα and Purβ decreased endogenous Sp3 and Pur protein levels and increased βMyHC reporter gene expression in C2C12 myotubes. Immunoprecipitation assays revealed an association between endogenous Purα, Purβ, and Sp3, while chromatin immunoprecipitation assays demonstrated Purα, Purβ, and Sp3 binding to the βMyHC proximal promoter region harboring the dβNRE-S and C-rich elements in vivo. These data demonstrate that Pur proteins collaborate with Sp3 to regulate a transcriptional program that enables muscle cells to remodel their phenotype.

scholarly journals Evidence of MyomiR network regulation of β-myosin heavy chain gene expression during skeletal muscle atrophy

2009 ◽  
Vol 39 (3) ◽  
pp. 219-226 ◽  
Author(s):  
John J. McCarthy ◽  
Karyn A. Esser ◽  
Charlotte A. Peterson ◽  
Esther E. Dupont-Versteegden
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Myosin Heavy Chain ◽  
Muscle Atrophy ◽  
Soleus Muscle ◽  
Heavy Chain ◽  
Hindlimb Suspension ◽  
Chain Gene ◽  
Heavy Chain Gene ◽  
Myosin Heavy Chain Gene

There is a growing recognition that noncoding RNAs (ncRNA) play an important role in the regulation of gene expression. A class of small (19–22 nt) ncRNAs, known as microRNAs (miRs), have received a great deal of attention lately because of their ability to repress gene expression through a unique posttranscriptional 3′-untranslated region (UTR) mechanism. The objectives of the current study were to identify miRs expressed in the rat soleus muscle and determine if their expression was changed in response to hindlimb suspension. Comprehensive profiling revealed 151 miRs were expressed in the soleus muscle and expression of 18 miRs were significantly ( P < 0.01) changed after 2 and/or 7 days of hindlimb suspension. The significant decrease (16%) in expression of muscle-specific miR-499 in response to hindlimb suspension was confirmed by RT-PCR and suggested activation of the recently proposed miR encoded by myosin gene (MyomiR) network during atrophy. Further analysis of soleus muscle subjected to hindlimb suspension for 28 days provided evidence consistent with MyomiR network repression of β-myosin heavy chain gene (β-MHC) expression. The significant downregulation of network components miR-499 and miR-208b by 40 and 60%, respectively, was associated with increased expression of Sox6 (2.2-fold) and Purβ (23%), predicted target genes of miR-499 and known repressors of β-MHC expression. A Sox6 3′-UTR reporter gene confirmed Sox6 is a target gene of miR-499. These results further expand the role of miRs in adult skeletal muscle and are consistent with a model in which the MyomiR network regulates slow myosin expression during muscle atrophy.

Sign in / Sign up

Export Citation Format

Share Document