Comprehensive Physiology Wiley Online Library

Regulation of Gene Expression in Skeletal Muscle by Contractile Activity

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Theoretical and Kinetic Considerations
2 Experimental Systems and Models for Study of Gene Regulation by Contractile Activity
2.1 Human Investigations
2.2 Animal Studies
2.3 Studies in Cell Culture
3 What Genes are Regulated by Contractile Activity?
3.1 Sarcomeric Proteins
3.2 Enzymes of Glycolysis
3.3 Mitochondrial Proteins
3.4 Transcription Factors
3.5 Growth Factors and Receptors
4 Mechanisms of Gene Regulation
4.1 Definitions
4.2 Transcription
4.3 RNA Processing, Targeting, and Stability
4.4 Translational and Posttranslational Control
5 Messengers and Signal Transduction Pathways
5.1 Calcium
5.2 Hydrogen Ion
5.3 Energy Charge/Phosphorylation Potential
5.4 Redox Potential
5.5 Oxygen Tension
5.6 Mechanical Stretch
5.7 Receptor Linked Signaling Pathways
6 Special Pathways for Control of Mitochondrial Genes
7 Conclusions
Figure 1. Figure 1.

Control of gene expression: potential messengers generated within contracting skeletal myofibers. Acetylcholine (ACh) released from the motor nerve binds its receptor and triggers membrane depolarization, release of calcium (Ca2+) from sarcoplasmic reticulum (SR) stores, and myofiber contractions. Mechanical stresses and metabolic events resulting from contractile activity generate other potential intracellular messengers. Additional extracellular messengers released by the motor nerve or arising from other sources initiate receptor linked signaling pathways. ARIA, acetylcholine receptor inducing activity; CNTF, ciliary neurotrophic factor; CGRP, calcitonin generelated peptide; NE, norepinephrine; EPI, epinephrine; ECM, extracellular matrix; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; PKC, protein kinase C; CAM‐K, calcium/calmodulin kinase.

Figure 2. Figure 2.

Steps at which gene expression may be controlled.

Figure 3. Figure 3.

Kinetic features of the regulation of mRNA abundance by a constant or intermittent stimulus. A, The effect of a continuous stimulus (e.g., chronic motor nerve stimulation) on abundance of a specific mRNA is plotted as a function of time. Assumptions in this model include: the induction mechanism is triggered immediately when the stimulus is applied; the mRNA half life is 12 h; and mRNA degradation is a first‐order process in which the degradation rate constant is unaffected by the stimulus. It is notable that 5 half‐lives (2.5 days) are required before ∼97% of the new steady‐state level is achieved, and 50% of the adaptive increase in [mRNA] is lost during the first half‐life after the stimulus is removed. The time required to reach steady state following initiation or withdrawal of the stimulus will be longer with more stable messages and shorter with mRNAs that degrade rapidly (e.g., early response gene products). B and C, The predicted response to an intermittent stimulus (e.g., treadmill running) delivered for only a fraction of each day. The same assumptions as in A apply. Much of the increase evoked by each stimulus period is lost prior to the next stimulus, and changes in mRNA abundance accrue more slowly than with continuous application of the stimulus.

Figure 4. Figure 4.

Empirical time course of changes in mRNA abundance evoked by continuous motor nerve stimulation of rabbit tibialis anterior skeletal muscles. Changes in mRNA concentrations (per fiber) are plotted schematically as a function of time following the onset of the stimulus (nonlinear scale). A large but transient induction of immediate early gene (IEG) expression occurs within the first day. Expression of several glycolytic enzymes (GLYC) achieves a new (lower) steady state within the first 5 days. Genes encoding slow isoforms of sarcomeric (SARC) proteins are up‐regulated to a new and higher steady state with a somewhat slower time course. Genes encoding mitochondrial (MITO) proteins exhibit a more complex pattern: a period of induction to markedly elevated mRNA concentrations, a plateau phase, and then a decline to a steady state that is above basal levels but below the apogee reached from 3–6 weeks after the onset of nerve stimulation. This figure is based on results from several laboratories, as referenced in the text and tables, with summary data presented in semiquantitative and schematic form only.

Figure 5. Figure 5.

Control of transcription factor activity by signals arising within contracting skeletal myofibers. At the first step in a cascade of gene regulatory events, a preexisting pool of a specific transcription factor (TxF) is present within the cell but is functionally inactive in resting muscles. Nerve stimulation and contractile activity trigger a signaling pathway, the culmination of which is the activation of TxF such that it can bind its cognate response element and induce transcription of a target gene (Gene A). The activation of TxF may be based on translocation from the cytoplasm to the nucleus; unmasking of a DNA binding domain (with or without release from an inhibitory factor); or unmasking of a previously nonfunctional trans‐activation domain. In this scenario, Gene A itself encodes a transcription factor, the synthesis of which subsequently regulates downstream genes (Gene B and Gene C). Examples of genetic control mechanisms that function in this manner are described in the text.

Figure 6. Figure 6.

Putative secondary events in the control of gene expression by contractile activity in skeletal muscles. Primary messengers illustrated in Figure evoke secondary responses that function as intermediate steps in the response to work overload. Such secondary events are likely to include the elaboration by the myofiber of peptide growth factors (e.g., IGF‐1); the induction of immediate early genes and other transcription factors; the increased synthesis of ribosomal RNA and proteins that alter the protein synthetic capacity of the cell; and the production of nuclear gene products that modulate replication or transcription of mitochondrial DNA, or that regulate translation, assembly, or stability of mitochondrial proteins.

Figure 7. Figure 7.

Steps in the cascade of events by which motor nerve activity leads to physiologically relevant alterations of skeletal muscles.



Figure 1.

Control of gene expression: potential messengers generated within contracting skeletal myofibers. Acetylcholine (ACh) released from the motor nerve binds its receptor and triggers membrane depolarization, release of calcium (Ca2+) from sarcoplasmic reticulum (SR) stores, and myofiber contractions. Mechanical stresses and metabolic events resulting from contractile activity generate other potential intracellular messengers. Additional extracellular messengers released by the motor nerve or arising from other sources initiate receptor linked signaling pathways. ARIA, acetylcholine receptor inducing activity; CNTF, ciliary neurotrophic factor; CGRP, calcitonin generelated peptide; NE, norepinephrine; EPI, epinephrine; ECM, extracellular matrix; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; PKC, protein kinase C; CAM‐K, calcium/calmodulin kinase.



Figure 2.

Steps at which gene expression may be controlled.



Figure 3.

Kinetic features of the regulation of mRNA abundance by a constant or intermittent stimulus. A, The effect of a continuous stimulus (e.g., chronic motor nerve stimulation) on abundance of a specific mRNA is plotted as a function of time. Assumptions in this model include: the induction mechanism is triggered immediately when the stimulus is applied; the mRNA half life is 12 h; and mRNA degradation is a first‐order process in which the degradation rate constant is unaffected by the stimulus. It is notable that 5 half‐lives (2.5 days) are required before ∼97% of the new steady‐state level is achieved, and 50% of the adaptive increase in [mRNA] is lost during the first half‐life after the stimulus is removed. The time required to reach steady state following initiation or withdrawal of the stimulus will be longer with more stable messages and shorter with mRNAs that degrade rapidly (e.g., early response gene products). B and C, The predicted response to an intermittent stimulus (e.g., treadmill running) delivered for only a fraction of each day. The same assumptions as in A apply. Much of the increase evoked by each stimulus period is lost prior to the next stimulus, and changes in mRNA abundance accrue more slowly than with continuous application of the stimulus.



Figure 4.

Empirical time course of changes in mRNA abundance evoked by continuous motor nerve stimulation of rabbit tibialis anterior skeletal muscles. Changes in mRNA concentrations (per fiber) are plotted schematically as a function of time following the onset of the stimulus (nonlinear scale). A large but transient induction of immediate early gene (IEG) expression occurs within the first day. Expression of several glycolytic enzymes (GLYC) achieves a new (lower) steady state within the first 5 days. Genes encoding slow isoforms of sarcomeric (SARC) proteins are up‐regulated to a new and higher steady state with a somewhat slower time course. Genes encoding mitochondrial (MITO) proteins exhibit a more complex pattern: a period of induction to markedly elevated mRNA concentrations, a plateau phase, and then a decline to a steady state that is above basal levels but below the apogee reached from 3–6 weeks after the onset of nerve stimulation. This figure is based on results from several laboratories, as referenced in the text and tables, with summary data presented in semiquantitative and schematic form only.



Figure 5.

Control of transcription factor activity by signals arising within contracting skeletal myofibers. At the first step in a cascade of gene regulatory events, a preexisting pool of a specific transcription factor (TxF) is present within the cell but is functionally inactive in resting muscles. Nerve stimulation and contractile activity trigger a signaling pathway, the culmination of which is the activation of TxF such that it can bind its cognate response element and induce transcription of a target gene (Gene A). The activation of TxF may be based on translocation from the cytoplasm to the nucleus; unmasking of a DNA binding domain (with or without release from an inhibitory factor); or unmasking of a previously nonfunctional trans‐activation domain. In this scenario, Gene A itself encodes a transcription factor, the synthesis of which subsequently regulates downstream genes (Gene B and Gene C). Examples of genetic control mechanisms that function in this manner are described in the text.



Figure 6.

Putative secondary events in the control of gene expression by contractile activity in skeletal muscles. Primary messengers illustrated in Figure evoke secondary responses that function as intermediate steps in the response to work overload. Such secondary events are likely to include the elaboration by the myofiber of peptide growth factors (e.g., IGF‐1); the induction of immediate early genes and other transcription factors; the increased synthesis of ribosomal RNA and proteins that alter the protein synthetic capacity of the cell; and the production of nuclear gene products that modulate replication or transcription of mitochondrial DNA, or that regulate translation, assembly, or stability of mitochondrial proteins.



Figure 7.

Steps in the cascade of events by which motor nerve activity leads to physiologically relevant alterations of skeletal muscles.

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R. Sanders Williams, P. Darrell Neufer. Regulation of Gene Expression in Skeletal Muscle by Contractile Activity. Compr Physiol 2011, Supplement 29: Handbook of Physiology, Exercise: Regulation and Integration of Multiple Systems: 1124-1150. First published in print 1996. doi: 10.1002/cphy.cp120125