Circadian Rhythms, Skeletal Muscle Molecular Clocks, Exercise
The molecular mechanism underlying circadian rhythms is a gene-regulatory network composed of transcriptional-translational feedback loops referred to as the "core clock". The molecular clock components comprising the positive arm of the core clock are two members of the PAS-bHLH family of transcription factors, Clock (Circadian locomotor output control kaput) and Bmal1 (Brain muscle arnt-like1). The BMAL1 protein is expressed in a circadian pattern in both the suprachiasmatic nucleus (SCN) and peripheral tissues. CLOCK protein levels do not oscillate in the SCN and only in some peripheral tissues. However, the nuclear to cytosolic distribution of CLOCK is circadian in its pattern, with highest levels of CLOCK in the nucleus occurring in the light phase in mice. The CLOCK:BMAL1 heterodimer activates transcription of additional core clock genes Period (Per1, Per2, and Per3) and Cryptochrome (Cry1 and Cry2) by binding to E-box (CACGTG) sequences in the regulatory region of these genes. The CRY and PER proteins constitute the negative arm of the core molecular clock by forming multimers that inhibit CLOCK:BMAL1 transcriptional activity on translocation to the nucleus. A schematic diagram of the molecular clock mechanism is shown in Figure 1.
(Enlarge Image)
Figure 1.
The core circadian clock is an autoregulatory transcriptional feedback loop composed of transcription factors CLOCK and Bmal1 and their target genes Per1, Per2, Cry1, and Cry2. The CLOCK:Bmal1 heterodimer also functions to drive transcription of Rev-erbα and Rorα, which, in turn, either repress or activate Bmal1 transcription, respectively. The CLOCK:Bmal1 heterodimer also regulates downstream targets known as clock-controlled genes (CCG). The kinases casein kinase 1ε (CK1ε) and AMP kinase (AMPK) phosphorylate PER(CK1D) and CRY(AMPK) proteins to promote polyubiquitination by E3 ubiquitin ligase complexes. PER and CRY proteins are then degraded by the 26S proteasome complex. CLOCK, circadian locomotor output control kaput; Bmal1, brain muscle arnt-like 1.
Additional components to the core molecular clock family include the orphan nuclear receptors Rora (RAR-related orphan receptor-α) and Rev-erb α/β. These gene products function to link the feedback loops by activating (Rora) or repressing (Rev-erb) Bmal1 transcription. Most recently, studies have added new elements, known as E3 ligases (e.g., Fbxl3), to the core molecular clock, and these elements function by changing the stability of the PER and CRY proteins. In addition to their role in timekeeping, components of the core clock (Bmal1 and Clock) also have been shown to regulate the expression of genes that do not function in timekeeping transcriptionally, and these genes are designated as clock-controlled genes (CCGs). Although the identity of all the direct clock-controlled genes in a specific tissue, like skeletal muscle, has not been defined, they often encode transcription factors (e.g., MyoD1) or proteins that control rate-limiting steps in cell physiology (e.g., PBEF, the rate-limiting enzyme in the NAD+ salvage pathway). For more detailed reviews of the molecular clock mechanism, there are several recent reviews by other groups.
The Molecular Clock in Mammals
The molecular mechanism underlying circadian rhythms is a gene-regulatory network composed of transcriptional-translational feedback loops referred to as the "core clock". The molecular clock components comprising the positive arm of the core clock are two members of the PAS-bHLH family of transcription factors, Clock (Circadian locomotor output control kaput) and Bmal1 (Brain muscle arnt-like1). The BMAL1 protein is expressed in a circadian pattern in both the suprachiasmatic nucleus (SCN) and peripheral tissues. CLOCK protein levels do not oscillate in the SCN and only in some peripheral tissues. However, the nuclear to cytosolic distribution of CLOCK is circadian in its pattern, with highest levels of CLOCK in the nucleus occurring in the light phase in mice. The CLOCK:BMAL1 heterodimer activates transcription of additional core clock genes Period (Per1, Per2, and Per3) and Cryptochrome (Cry1 and Cry2) by binding to E-box (CACGTG) sequences in the regulatory region of these genes. The CRY and PER proteins constitute the negative arm of the core molecular clock by forming multimers that inhibit CLOCK:BMAL1 transcriptional activity on translocation to the nucleus. A schematic diagram of the molecular clock mechanism is shown in Figure 1.
(Enlarge Image)
Figure 1.
The core circadian clock is an autoregulatory transcriptional feedback loop composed of transcription factors CLOCK and Bmal1 and their target genes Per1, Per2, Cry1, and Cry2. The CLOCK:Bmal1 heterodimer also functions to drive transcription of Rev-erbα and Rorα, which, in turn, either repress or activate Bmal1 transcription, respectively. The CLOCK:Bmal1 heterodimer also regulates downstream targets known as clock-controlled genes (CCG). The kinases casein kinase 1ε (CK1ε) and AMP kinase (AMPK) phosphorylate PER(CK1D) and CRY(AMPK) proteins to promote polyubiquitination by E3 ubiquitin ligase complexes. PER and CRY proteins are then degraded by the 26S proteasome complex. CLOCK, circadian locomotor output control kaput; Bmal1, brain muscle arnt-like 1.
Additional components to the core molecular clock family include the orphan nuclear receptors Rora (RAR-related orphan receptor-α) and Rev-erb α/β. These gene products function to link the feedback loops by activating (Rora) or repressing (Rev-erb) Bmal1 transcription. Most recently, studies have added new elements, known as E3 ligases (e.g., Fbxl3), to the core molecular clock, and these elements function by changing the stability of the PER and CRY proteins. In addition to their role in timekeeping, components of the core clock (Bmal1 and Clock) also have been shown to regulate the expression of genes that do not function in timekeeping transcriptionally, and these genes are designated as clock-controlled genes (CCGs). Although the identity of all the direct clock-controlled genes in a specific tissue, like skeletal muscle, has not been defined, they often encode transcription factors (e.g., MyoD1) or proteins that control rate-limiting steps in cell physiology (e.g., PBEF, the rate-limiting enzyme in the NAD+ salvage pathway). For more detailed reviews of the molecular clock mechanism, there are several recent reviews by other groups.
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