The functional significance of the skeletal muscle clock: lessons from Bmal1 knockout models
© The Author(s). 2016
Received: 4 August 2016
Accepted: 28 September 2016
Published: 13 October 2016
The circadian oscillations of muscle genes are controlled either directly by the intrinsic muscle clock or by extrinsic factors, such as feeding, hormonal signals, or neural influences, which are in turn regulated by the central pacemaker, the suprachiasmatic nucleus of the hypothalamus. A unique feature of circadian rhythms in skeletal muscle is motor neuron-dependent contractile activity, which can affect the oscillation of a number of muscle genes independently of the muscle clock. The role of the intrinsic muscle clock has been investigated using different Bmal1 knockout (KO) models. A comparative analysis of these models reveals that the dramatic muscle wasting and premature aging caused by global conventional KO are not present in muscle-specific Bmal1 KO or in global Bmal1 KO induced in the adult, therefore must reflect the loss of Bmal1 function during development in non-muscle tissues. On the other hand, muscle-specific Bmal1 knockout causes impaired muscle glucose uptake and metabolism, supporting a major role of the muscle clock in anticipating the sleep-to-wake transition, when glucose becomes the predominant fuel for the skeletal muscle.
KeywordsSkeletal muscle Circadian rhythms Muscle clock Bmal1 knockout Muscle denervation Glucose uptake Glucose metabolism
Extrinsic control of circadian rhythms in the skeletal muscle: the role of motor activity
Peripheral oscillators, including the muscle clock, are synchronized by the SCN through a variety of signals, including daily variations in body temperature, humoral factors, and the autonomic nervous system (reviewed in ). Oscillations of tissue-specific circadian genes are controlled either directly by the intrinsic peripheral clocks or indirectly by extrinsic factors (Fig. 1b). For example, inducible liver-specific repression of Bmal1 transcription abrogates the oscillation of most circadian liver genes, showing that they are directly controlled by the hepatocyte clock; however, a number of other genes continue oscillating even in the absence of a functional liver clock, showing that they are controlled by extrinsic factors . Feeding has a dominant role in setting the phase of peripheral oscillators, as temporal feeding restriction, induced by offering food only during the light phase, radically changes the phase of both core clock genes and other circadian genes in peripheral tissues of mice , including the skeletal muscle . Plasma glucocorticoid and body temperature rhythms are also involved in the synchronization of peripheral clocks . Another potential extrinsic circadian signal, which is unique to skeletal muscle, is motor neuron-dependent contractile activity.
Locomotor activity has traditionally been used both in mice and in flies as a readout of the circadian timing system. One may wonder whether motor neuron activity regulates the intrinsic muscle clock and/or other muscle cycling genes. Indeed, a phase distribution analysis of the circadian muscle transcriptome revealed that the largest cluster of rhythmic genes is found at the midpoint of the active phase . Exercise was found to affect both the amplitude and the phase of the circadian clock in the skeletal muscle (reviewed in [9, 10]). However, interpretation of these results is complicated by the fact that exercise causes systemic effects, such as hormonal changes and increased body temperature, which are known to affect the peripheral oscillators. One-leg exercise in humans allowed for direct comparisons between active and inactive legs in the same individuals, thus excluding the potential contribution of systemic effects of exercise: the expression of core clock genes and downstream targets was modified in the exercised but not in the non-exercised contralateral leg; however, only two time points were examined in this study .
The calcineurin-NFAT signaling pathway is involved in the nerve activity-dependent regulation of muscle fiber-type-specific gene programs (reviewed in ), and one member of the NFAT family, NFATc1, acts as a slow-type nerve activity sensor in vivo [15, 16], whereas other members of the NFAT family are also responsive to fast-type nerve activity and might thus contribute to modulate the fast fiber phenotype . An NFATc1-GFP fusion protein, when electroporated in skeletal muscles in vivo shows a predominantly cytoplasmic localization in the fast tibialis anterior muscle but a nuclear localization in the slow soleus. A rapid nuclear translocation of NFATc1 can be induced by electrical stimulation of tibialis anterior with an impulse pattern typical of slow motor neurons, while denervation causes a rapid nuclear export of NFATc1 in soleus . NFAT nuclear translocation and transcriptional activity has been recently analyzed during the day-night cycle . NFATc1-GFP shows an accumulation in mouse soleus myonuclei during the dark phase with a peak at Zeitgeber (ZT)16, and a similar circadian oscillation of luciferase activity is seen after electroporation of an NFAT-luciferase construct but with a 4–8-h delay. The NFAT target gene, Rcan1.4, shows a similar circadian oscillation with a peak during the dark phase, which is drastically decreased in denervated muscle (Fig. 2). Interestingly, Rcan1.4 circadian oscillation is unchanged in muscle-specific Bmal1 mKO muscles, supporting the notion that Rcan1.4 is a circadian muscle gene that is dependent on activity but independent of the core oscillator. It is possible that some of the changes induced by denervation may not reflect a direct effect of the loss of nerve activity but might be due to the transcriptional remodeling of gene expression that accompanies the denervation process. However, this possibility seems unlikely for NFAT target genes, as a drastic reduction of Rcan1.4 gene expression during the dark phase is already detected at 12 h after nerve section, before any significant change in transcriptional programs has taken place in denervated muscles .
The role of the intrinsic muscle clock: lessons from Bmal1 knockout models
Global phenotypes of different Bmal1 knockout models
Whole body Bmal1 KO
Muscle-specific Bmal1 KO
Standard + rescue with mBmal1 a
Circadian locomotor rhythm
Total activity level
Muscle fiber CSA
Muscle force (normalized)
Muscle fiber-type profile (fast muscles)
Mice with whole body Bmal1 KO, generated by standard methods leading to deletion of the gene in germinal cells, stop growing around 16 weeks of age, display progressive and dramatic muscle atrophy and decreased total activity level, and die between 26 and 52 weeks of age with signs of premature aging, including arthropathy, decreased hair growth, ocular abnormalities such as cataracts, and neurodegeneration with brain astrogliosis [18–20]. Bmal1 KO also causes altered metabolism, including altered response to insulin [21, 22] and ectopic fat accumulation in the skeletal muscle . Some of these changes could be due to increased oxidative stress, since the loss of Bmal1 is known to cause accumulation of reactive oxygen species [19, 24] and antioxidant treatment was found to ameliorate symptoms of premature aging . Muscle structure and function is altered in these mice even at early stages of postnatal development: at 12–14 weeks of age, muscle force is decreased, ultrastructural organization of thick and thin filament appears disrupted, and mitochondrial volume and respiratory function are decreased . It was suggested that these changes are due to loss of function of the muscle-specific regulatory factor MyoD, because similar changes were found in Myod1 null mice and Myod1 was reported to be a target of BMAL1 and to lose its circadian oscillation in Bmal1 KO mice . However, this interpretation is in contrast with a subsequent study on a muscle-specific Bmal1 KO model, obtained by crossing a mouse line bearing a floxed Bmal1 with an Mlc1f-Cre line, bearing Cre recombinase driven by the myosin light chain 1 fast promoter . These mice show drastic reduction of Bmal1 transcripts in the skeletal muscle but not in the heart and other organs; however, they have normal life span and body weight with no obvious sign of premature aging. Muscle histology and ultrastructure are normal, and muscle weight is even increased with a slight decrease in normalized muscle force . These findings suggest that the dramatic muscle atrophy found in whole body Bmal1 KO mice cannot result from a disrupted muscle clock or from loss of cell-autonomous function of Bmal1 in muscle fibers (see also ). In addition, Myod1 gene expression is increased rather than decreased in these mice and maintains its circadian oscillation with a peak during the dark phase of the cycle (Fig. 2). A similar effect, with an even greater upregulation of Myod1, is seen after denervation. Based on these results, it seems unlikely that MyoD can mediate the effect of BMAL1 function on the skeletal muscle, as previously suggested . On the other hand, Myod1 gene expression is apparently controlled by feeding, as Myod1 transcripts are strongly downregulated by fasting, under conditions when Bmal1 transcripts maintain their normal levels and circadian pattern of expression .
Further insight into the function of Bmal1 in muscle fibers was obtained by inducible Bmal1 KO models. A ubiquitously inducible KO model was generated by crossing a floxed Bmal1 line with a tamoxifen-inducible universal Cre line . Tamoxifen treatment was started in 3-month-old mice leading to Bmal1 inactivation in all tissues at an adult stage, with the skeletal muscles showing a 99 % reduction of Bmal1 mRNA levels at Zeitgeber time 0 (ZT0, lights on), when Bmal1 expression is high. These mice showed no significant difference in life span or body and organ weight when compared to control, suggesting that the dramatic phenotype seen in conventional Bmal1 KO mice results from BMAL1 function during development. Hair growth is normal, and there is no sign of age-dependent arthropathy or calcification, although brain astrogliosis and ocular abnormalities, similar to those observed with prenatal Bmal1 KO , were also evident after postnatal Bmal1 depletion . No difference was seen in glucose tolerance test (GTT) and insulin tolerance test (ITT) between KO and control mice. These results indicate that most phenotypes in conventional Bmal1 KO mice, previously attributed to disruption of circadian rhythms, reflect the loss of properties of BMAL1 during early development and are probably independent of its role in the clock (see below). However, BMAL1 appears to have a direct function in the eye and central nervous system irrespective of developmental issues and probably due to increased oxidative stress . Muscle-specific inducible models were generated by crossing a floxed Bmal1 line with a tamoxifen-inducible Cre driven by the human α-actin promoter, thus inducing Bmal1 inactivation exclusively in the skeletal muscle at an adult stage . These mice have an essentially normal phenotype with respect to life span, body weight, and muscle mass (Table 1); however, they show altered glucose metabolism (see below). Muscle force and the proportion of type 2B fibers were decreased in these mice, whereas fiber size was unchanged even at 12 months of age and centrally nucleated fibers were not detected .
Taken together, these studies suggest that the dramatic phenotype observed in the global Bmal1 KO, characterized by premature aging and death, with reduced body weight and muscle wasting, reflects the loss of Bmal1 function during development in non-muscle tissues. Two KO models support this conclusion. First, muscle-specific Bmal1 KO, leading to Bmal1 deletion since early developmental stages selectively in the skeletal muscle, does not induce significant changes with the exception of altered muscle metabolism , pointing to a major effect of Bmal1 in non-muscle tissues in the pathogenesis of sarcopenia, premature aging, and reduced life span. Second, these changes are also absent when Bmal1 KO is induced ubiquitously at an adult stage, therefore must reflect the loss of Bmal1 during development .
Role of the muscle clock in glucose uptake and metabolism
The tissue-specific role of BMAL1 in regulating insulin sensitivity in muscle cells is supported by studies on cultured C2C12 myotubes . In these cells, insulin sensitivity is reduced by knockdown of Clock or Bmal1, while the insulin resistance induced by palmitate is improved by Clock and Bmal1 overexpression . These effects appear to be mediated by SIRT1, which is a target of CLOCK and BMAL1, as shown by the finding that (i) Sirt1 knockdown blocks the improvement induced by Clock and Bmal1 overexpression on the palmitate-dependent insulin resistance and (ii) Sirt1 overexpression ameliorates insulin resistance induced by knockdown of Clock or Bmal1.
The comparative analysis summarized in Table 1 shows that the muscle phenotype is variably affected in different Bmal1 KO models. In particular, the dramatic muscle wasting and premature aging found in the global conventional KO are not present in muscle-specific Bmal1 KO or in global KO induced in the adult, thus must reflect the loss of Bmal1 function during development and in non-muscle tissues. These findings indicate that the intrinsic muscle clock is dispensable for muscle growth and that its inactivation does not cause premature aging and reduced life span. The fact that core clock genes are not oscillating in embryonic tissues points to possible non-clock functions of Bmal1 during development, such as the recently identified BMAL1 role in the control of protein synthesis. On the other hand, Bmal1 circadian oscillation in the skeletal muscle is involved in adult muscle metabolism. In particular, two models of muscle-specific inactivation of Bmal1 suggest that the intrinsic muscle clock controls both glucose uptake and glucose metabolism in the skeletal muscle and support the conclusion that “a major physiological role of the muscle clock is to prepare the tissue for the transition from the rest/fasting phase to the active/feeding phase, when glucose becomes the predominant fuel for skeletal muscle” . It will be important to confirm this conclusion with muscle-specific KO of other clock genes, e.g., double KO of Per1 and Per2, or Cry1 and Cry2, in order to establish unambiguously that the changes in muscle metabolism induced by Bmal1 KO result from the disruption of the muscle clock and not from specific functions of Bmal1.
Note added in proof
After submission of our manuscript we became aware of a recent study describing another muscle-specific Bmal1 KO model obtained by crossing floxed Bmal1 with MCK-Cre mice . These mice have a normal life span, thus confirming the results of Dyar et al. , and show a denervation-induced increased in Myod1 expression similar to that of wild type mice.
Casein kinase 2
Glucose transporter 4
Glucose tolerance test
Insulin tolerance test
PDH kinase 4
PDH phosphatase 1
Availability of data and materials
SS, BB, and KAD contributed to the writing and editing of this manuscript. All authors read and approved the manuscript.
The authors declare that they have no competing interests.
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