The role of calcium and calcium/calmodulin-dependent kinases in skeletal muscle plasticity and mitochondrial biogenesis

Intracellular Ca2+plays an important role in skeletal muscle excitation–contraction coupling and also in excitation–transcription coupling. Activity-dependent alterations in muscle gene expression as a result of increased load (i.e. resistance or endurance training) or decreased activity (i.e. immobilization or injury) are tightly linked to the level of muscle excitation. Differential expression of genes in slow- and fast-twitch fibres is also dependent on fibre activation. Both these biological phenomena are, therefore, tightly linked to the amplitude and duration of the Ca2+transient, a signal decoded downstream by Ca2+-dependent transcriptional pathways. Evidence is mounting that the calcineurin–nuclear factor of activated T-cells pathway and the Ca2+/calmodulin-dependent kinases (CaMK) II and IV play important roles in regulating oxidative enzyme expression, mitochondrial biogenesis and expression of fibre-type specific myofibrillar proteins. CaMKII is known to decode frequency-dependent information and is activated during hypertrophic growth and endurance adaptations. Thus, it was hypothesized that CaMKII, and possibly CaMKIV, are down regulated during muscle atrophy and levels of expression of CaMKIIα, -IIβ, -IIγ and -IV were assessed in skeletal muscles from young, aged and denervated rats. The results indicate that CaMKIIγ, but not CaMKIIα or -β, is up regulated in aged and denervated soleus muscle and that CaMKIV is absent in skeletal but not cardiac muscle. Whether CaMKIIγ up-regulation is part of the pathology of wasting or a result of some adaptational response to atrophy is not known. Future studies will be important in determining whether insights from the adaptational response of muscle to increased loads will provide pharmacological approaches for increasing muscle strength or endurance to counter muscle wasting.

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Impact of hot and cold exposure on human skeletal muscle gene expression

Applied Physiology Nutrition and Metabolism ◽

10.1139/apnm-2016-0415 ◽

2017 ◽

Vol 42 (3) ◽

pp. 319-325 ◽

Cited By ~ 6

Author(s):

Roksana B. Zak ◽

Robert J. Shute ◽

Matthew W.S. Heesch ◽

D. Taylor La Salle ◽

Matthew P. Bubak ◽

...

Keyword(s):

Gene Expression ◽

Skeletal Muscle ◽

Mitochondrial Biogenesis ◽

Room Temperature ◽

Environmental Temperature ◽

Human Model ◽

Whole Body ◽

Muscle Gene Expression ◽

Muscle Gene ◽

The Impact

Many human diseases lead to a loss of skeletal muscle metabolic function and mass. Local and environmental temperature can modulate the exercise-stimulated response of several genes involved in mitochondrial biogenesis and skeletal muscle function in a human model. However, the impact of environmental temperature, independent of exercise, has not been addressed in a human model. Thus, the purpose of this study was to compare the effects of exposure to hot, cold, and room temperature conditions on skeletal muscle gene expression related to mitochondrial biogenesis and muscle mass. Recreationally trained male subjects (n = 12) had muscle biopsies taken from the vastus lateralis before and after 3 h of exposure to hot (33 °C), cold (7 °C), or room temperature (20 °C) conditions. Temperature had no effect on most of the genes related to mitochondrial biogenesis, myogenesis, or proteolysis (p > 0.05). Core temperature was significantly higher in hot and cold environments compared with room temperature (37.2 ± 0.1 °C, p = 0.001; 37.1 ± 0.1 °C, p = 0.013; 36.9 ± 0.1 °C, respectively). Whole-body oxygen consumption was also significantly higher in hot and cold compared with room temperature (0.38 ± 0.01 L·min−1, p < 0.001; 0.52 ± 0.03 L·min−1, p < 0.001; 0.35 ± 0.01 L·min−1, respectively). In conclusion, these data show that acute temperature exposure alone does not elicit significant changes in skeletal muscle gene expression. When considered in conjunction with previous research, exercise appears to be a necessary component to observe gene expression alterations between different environmental temperatures in humans.

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Mitochondrial Biogenesis in Striated Muscle

Canadian Journal of Applied Physiology ◽

10.1139/h94-002 ◽

1994 ◽

Vol 19 (1) ◽

pp. 12-48 ◽

Cited By ~ 27

Author(s):

David A. Hood ◽

Atila Balaban ◽

Michael K. Connor ◽

Elaine E. Craig ◽

Mary L. Nishio ◽

...

Keyword(s):

Skeletal Muscle ◽

Mitochondrial Biogenesis ◽

Protein Import ◽

Striated Muscle ◽

Cellular Systems ◽

Future Research ◽

Striated Muscles ◽

Muscle Gene Expression ◽

Key Words Heart ◽

Muscle Gene

Mitochondrial biogenesis (synthesis) has been observed to occur in skeletal muscle in response to chronic use. It also occurs in cardiac muscle during growth and hypertrophy, and it may be impaired during the aging process. This review summarizes the literature on the processes of mitochondrial biogenesis at the biochemical and molecular levels, with particular reference to striated muscles. Mitochondrial biogenesis involves the expression of nuclear and mitochondrial genes and the coordination of these two genomes, the synthesis of proteins and phospholipids and their import into the organelle, and the incorporation of these lipids and proteins into their appropriate locations within the matrix, inner or outer membranes. The emphasis is on the regulation of these events, with information derived in part from other cellular systems. Although descriptions of mitochondrial content changes in heart and skeletal muscle during altered physiological states are plentiful, much work is needed at the molecular level to investigate the regulatory processes involved. A knowledge of biochemical and molecular biology techniques is essential for continued progress in the field. This is a promising area, and potential new avenues for future research are suggested. Key words: heart, skeletal muscle, gene expression, heme metabolism, protein import

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Role of Ca2+/calmodulin-dependent kinases in skeletal muscle plasticity

Journal of Applied Physiology ◽

10.1152/japplphysiol.00015.2005 ◽

2005 ◽

Vol 99 (2) ◽

pp. 414-423 ◽

Cited By ~ 132

Author(s):

Eva R. Chin

Keyword(s):

Skeletal Muscle ◽

Mitochondrial Biogenesis ◽

Muscle Activation ◽

Contractile Activity ◽

Fiber Type ◽

Specific Gene ◽

Muscle Plasticity ◽

Hypertrophic Growth ◽

Motor Activation ◽

Activity Dependent

In skeletal muscle, the increase in intracellular Ca2+ resulting from motor activation plays a key role in both contractile activity-dependent and fiber type-specific gene expression. These motor activation-dependent signals are linked to the amplitude and duration of the Ca2+ transients that are decoded downstream by Ca2+-dependent transcriptional pathways. Evidence is mounting that the Ca2+/calmodulin-dependent kinases (CaMKs) such as CaMKII play an important role in regulating oxidative enzyme expression, mitochondrial biogenesis, and expression of fiber type-specific myofibrillar proteins. CaMKIV has been shown to promote mitochondrial biogenesis and a mild fast-to-slow fiber type transition but has recently been shown to not be required for activity-dependent changes in muscle phenotype. CaMKII is known to decode frequency-dependent information and is activated during hypertrophic growth and endurance adaptations and also is upregulated during muscle atrophy. CaMKII has also been shown to remain active in a Ca2+-independent manner after acute and prolonged exercise, and, therefore, is implicated as a mechanism for muscle memory. This mechanism can sense altered functional demands and trigger activation of an adaptational response that is dose dependently related to the activation level. This class of enzymes may therefore be the ideal decoders of information encoded by the intensity, frequency, and duty cycle of muscle activation and thus translate level of muscle activation into phenotypic adaptations through regulation of important muscle genes.

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Energy sensing and regulation of gene expression in skeletal muscle

Journal of Applied Physiology ◽

10.1152/japplphysiol.01126.2005 ◽

2007 ◽

Vol 102 (2) ◽

pp. 529-540 ◽

Cited By ~ 52

Author(s):

Damien Freyssenet

Keyword(s):

Gene Expression ◽

Skeletal Muscle ◽

Energy Homeostasis ◽

Regulation Of Gene Expression ◽

Hypoxia Inducible Factor ◽

Peroxisome Proliferator ◽

Muscle Plasticity ◽

Muscle Gene Expression ◽

Energy Sensing ◽

Muscle Gene

Major modifications in energy homeostasis occur in skeletal muscle during exercise. Emerging evidence suggests that changes in energy homeostasis take part in the regulation of gene expression and contribute to muscle plasticity. A number of energy-sensing molecules have been shown to sense variations in energy homeostasis and trigger regulation of gene expression. The AMP-activated protein kinase, hypoxia-inducible factor 1, peroxisome proliferator-activated receptors, and Sirt1 proteins all contribute to altering skeletal muscle gene expression by sensing changes in the concentrations of AMP, molecular oxygen, intracellular free fatty acids, and NAD+, respectively. These molecules may therefore sense information relating to the intensity, duration, and frequency of muscle exercise. Mitochondria also contribute to the overall response, both by modulating the response of energy-sensing molecules and by generating their own signals. This review seeks to examine our current understanding of the roles that energy-sensing molecules and mitochondria can play in the regulation of gene expression in skeletal muscle.

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Pharmacological regulation of skeletal muscle gene expression

Nuclear Receptor Signaling Atlas Datasets ◽

10.1621/datasets.05002 ◽

2013 ◽

Author(s):

R Evans

Keyword(s):

Gene Expression ◽

Skeletal Muscle ◽

Muscle Gene Expression ◽

Pharmacological Regulation ◽

Muscle Gene

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Skeletal muscle gene expression in space‐flown rats

The FASEB Journal ◽

10.1096/fj.03-0419fje ◽

2004 ◽

Vol 18 (3) ◽

pp. 522-524 ◽

Cited By ~ 146

Author(s):

Takeshi Nikawa ◽

Kazumi Ishidoh ◽

Katsuya Hirasaka ◽

Ibuki Ishihara ◽

Madoka Ikemoto ◽

...

Keyword(s):

Gene Expression ◽

Skeletal Muscle ◽

Muscle Gene Expression ◽

Muscle Gene

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Effects of equine myostatin (MSTN) genotype variation on transcriptional responses in Thoroughbred skeletal muscle

Comparative Exercise Physiology ◽

10.3920/cep190009 ◽

2019 ◽

Vol 15 (5) ◽

pp. 327-338

Author(s):

K. Bryan ◽

L.M. Katz ◽

E.W. Hill

Keyword(s):

Skeletal Muscle ◽

Skeletal Muscle Fibre ◽

P Value ◽

Transcriptional Responses ◽

Myostatin Gene ◽

Muscle Gene Expression ◽

Gene Differential Expression ◽

Sine Insertion ◽

Significant Enrichment ◽

Muscle Gene

Myostatin gene (MSTN) variation influences distance aptitude in Thoroughbreds as a consequence of functional physiological effects including skeletal muscle fibre type and muscle hypertrophy variation. A promotor region short interspersed nuclear element (SINE) insertion, tagged by SNP g.66493737-C, alters MSTN mRNA expression. We tested the hypothesis that skeletal muscle gene expression varies among MSTN genotypes due to differential up- or down-stream gene signalling pathways that may be influenced by exercise and training and consequently contribute to variation in exercise phenotypes. Skeletal muscle biopsies were collected from Thoroughbreds previously genotyped for MSTN (n=35 CC, n=50 CT, n=9 TT) at three different time-points: untrained at rest (UR), untrained after exercise (UE) and trained at rest (TR). Gene differential expression (DE) was determined from RNAseq data using DESeq2 (Benjamini-Hochberg P-value <0.05). Functional over-representation analysis was performed in DAVID. In UR samples, one, nine and 47 genes were DE between CC vs CT, CT vs TT and C:C vs TT, respectively. The OSGEPL1 gene, located <250 Kb proximal to MSTN, was DE among all cohorts. Six genes were DE in UE between CC vs TT including OSGEPL1, FGF10 and COQ8A. There was significant enrichment for GO categories related to mitochondria in TR. Comparison of the exercise response (UR vs UE) revealed patterns of expression that were opposing; i.e. CHRNG was 0.857 log2FC in the TT cohort but 2.055 log2FC in the CC cohort. Genes located in proximity to MSTN and involved in mitochondrial function were most significantly different among genotype cohorts. Patterns of DE among genotypes suggests gene-regulated influence on the phenotype. Understanding these patterns may assist genotype-guided training strategies.

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Stable incorporation of a bacterial gene into adult rat skeletal muscle in vivo

AJP Cell Physiology ◽

10.1152/ajpcell.1990.258.3.c578 ◽

1990 ◽

Vol 258 (3) ◽

pp. C578-C581 ◽

Cited By ~ 33

Author(s):

D. B. Thomason ◽

F. W. Booth

Keyword(s):

Skeletal Muscle ◽

Leukemia Virus ◽

Rat Skeletal Muscle ◽

Bacterial Gene ◽

Muscle Gene Expression ◽

Adult Rat ◽

Foreign Genes ◽

Muscle Gene ◽

Beta Galactosidase

We have developed a novel technique to incorporate and stably express foreign genes in adult rat skeletal muscle in vivo. Endogeneous satellite cells in skeletal muscle regenerating from bupivacaine damage were infected with an injected retrovirus containing the Escherichia coli beta-galactosidase gene under the promoter control of the Moloney murine leukemia virus long-terminal repeat. Constitutive and stable expression of beta-galactosidase activity was observed in muscle fibers after 6 days and 1 mo of muscle regeneration. Two patterns of expression were observed, diffuse expression within fibers and focal expression associated with the sarcolemma. This technique will allow future experiments with muscle-specific genes and promoters to study the physiological regulation of skeletal muscle gene expression in the intact adult mammal. Furthermore, the technique of stimulating stem cell proliferation to allow retroviral-mediated gene transfer may be generally applicable to other tissues.

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