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Cited by 231Circadian rhythm and melatoninMetabolism, Diabetes, and CancerAdipose Tissue and Metabolism

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Muscle-specific loss of Bmal1 leads to disrupted tissue glucose metabolism and systemic glucose homeostasis

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Harfmann, Brianna D., Schroder, Elizabeth A., Kachman, Maureen T., Hodge, Brian A., Zhang, Xiping, Esser, Karyn A.·2016·Skeletal Muscle
DOI 10.1186/s13395-016-0082-xPMC PMC4969979
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Abstract

BACKGROUND: Diabetes is the seventh leading cause of death in the USA, and disruption of circadian rhythms is gaining recognition as a contributing factor to disease prevalence. This disease is characterized by hyperglycemia and glucose intolerance and symptoms caused by failure to produce and/or respond to insulin. The skeletal muscle is a key insulin-sensitive metabolic tissue, taking up ~80 % of postprandial glucose. To address the role of the skeletal muscle molecular clock to insulin sensitivity and glucose tolerance, we generated an inducible skeletal muscle-specific Bmal1 (-/-) mouse (iMSBmal1 (-/-)). RESULTS: Progressive changes in body composition (decreases in percent fat) were seen in the iMSBmal1 (-/-) mice from 3 to 12 weeks post-treatment as well as glucose intolerance and non-fasting hyperglycemia. Ex vivo analysis of glucose uptake revealed that the extensor digitorum longus (EDL) muscles did not respond to either insulin or 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) stimulation. RT-PCR and Western blot analyses demonstrated a significant decrease in mRNA expression and protein content of the muscle glucose transporter (Glut4). We also found that both mRNA expression and activity of two key rate-limiting enzymes of glycolysis, hexokinase 2 (Hk2) and phosphofructokinase 1 (Pfk1), were significantly reduced in the iMSBmal1 (-/-) muscle. Lastly, results from metabolomics analyses provided evidence of decreased glycolytic flux and uncovered decreases in some tricarboxylic acid (TCA) intermediates with increases in amino acid levels in the iMSBmal1 (-/-) muscle. These findings suggest that the muscle is relying predominantly on fat as a fuel with increased protein breakdown to support the TCA cycle. CONCLUSIONS: These data support a fundamental role for Bmal1, the endogenous circadian clock, in glucose metabolism in the skeletal muscle. Our findings have implicated altered molecular clock dictating significant changes in altered substrate metabolism in the absence of feeding or activity changes. The changes in body composition in our model also highlight the important role that changes in skeletal muscle carbohydrate, and fat metabolism can play in systemic metabolism.

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Fig. 1 Body composition but not behavior was altered in the iMSBmal1−/− mice. a Body weight and composition (lean and fat mass) at 3–5 weeks post-treatment (n = 17 iMSBmal1+/+, n = 20 iMSBmal1−/−). b Body weight and composition (lean and fat mass) at 10–12 weeks post-treatment (n = 12 iMSBmal1+/+, n = 15 iMSBmal1−/−). c Feeding (4 days) at 5 weeks post-treatment (n = 4 iMSBmal1+/+, n = 6 iMSBmal1−/−) and activity (3 days) at 5 and 10 weeks post-treatment (n = 5 iMSBmal1+/+, n = 5 iMSBmal1−/−)
Fig. 1 Body composition but not behavior was altered in the iMSBmal1−/− mice. a Body weight and composition (lean and fat mass) at 3–5 weeks post-treatment (n = 17 iMSBmal1+/+, n = 20 iMSBmal1−/−). b Body weight and composition (lean and fat mass) at 10–12 weeks post-treatment (n = 12 iMSBmal1+/+, n = 15 iMSBmal1−/−). c Feeding (4 days) at 5 weeks post-treatment (n = 4 iMSBmal1+/+, n = 6 iMSBmal1−/−) and activity (3 days) at 5 and 10 weeks post-treatment (n = 5 iMSBmal1+/+, n = 5 iMSBmal1−/−)CC BY · PubMed Central
Fig. 2 iMSBmal1−/− mice display altered systemic glucose handling. a Fasted blood glucose (n = 8/group (2 females and 6 males in both groups)). b Fasted blood insulin n = 7/group (3 females and 4 males in both groups). c Glucose tolerance depicted as blood glucose versus time post-glucose injection and area under the curve (n = 8/group (2 females and 6 males) in both groups). d Non-fasted blood glucose measured every 4 h for 24 h [n = 4 per time point: CT18 iMSBmal1+/+ n = 2 F/2 M; iMSBmal1−/− n = 2 F/2 M; CT22 iMSBmal1+/+ n = 4 M; iMSBmal1−/− n = 2 F/2 M; CT26 iMSBmal1+/+ n = 2 F/2 M; iMSBmal1−/− n = 1 F/3 M; CT30 iMSBmal1+/+ n = 1 F/3 M; iMSBmal1−/− n = 1 F/3 M; CT34 iMSBmal1+/+ n = 1 F/3 M; iMSBmal1−/− n = 1 F/3 M]
Fig. 2 iMSBmal1−/− mice display altered systemic glucose handling. a Fasted blood glucose (n = 8/group (2 females and 6 males in both groups)). b Fasted blood insulin n = 7/group (3 females and 4 males in both groups). c Glucose tolerance depicted as blood glucose versus time post-glucose injection and area under the curve (n = 8/group (2 females and 6 males) in both groups). d Non-fasted blood glucose measured every 4 h for 24 h [n = 4 per time point: CT18 iMSBmal1+/+ n = 2 F/2 M; iMSBmal1−/− n = 2 F/2 M; CT22 iMSBmal1+/+ n = 4 M; iMSBmal1−/− n = 2 F/2 M; CT26 iMSBmal1+/+ n = 2 F/2 M; iMSBmal1−/− n = 1 F/3 M; CT30 iMSBmal1+/+ n = 1 F/3 M; iMSBmal1−/− n = 1 F/3 M; CT34 iMSBmal1+/+ n = 1 F/3 M; iMSBmal1−/− n = 1 F/3 M]CC BY · PubMed Central
Fig. 3 Glucose uptake was diminished in the iMSBmal1−/− mice. a Insulin-stimulated glucose uptake in the EDL muscles using a maximum insulin dose and 20 min of exposure [n = 8 (2 F/6 M)/group]. b AICAR-stimulated glucose uptake in the EDL muscles after 40 min of exposure incubation media with or without AICAR n = 5 (5 F)/group
Fig. 3 Glucose uptake was diminished in the iMSBmal1−/− mice. a Insulin-stimulated glucose uptake in the EDL muscles using a maximum insulin dose and 20 min of exposure [n = 8 (2 F/6 M)/group]. b AICAR-stimulated glucose uptake in the EDL muscles after 40 min of exposure incubation media with or without AICAR n = 5 (5 F)/groupCC BY · PubMed Central
Fig. 4 Both mRNA and protein expression of the glucose transporter type 4 (Glut4/GLUT4) were decreased in the iMSBmal1 -/- mice. a mRNA expression of Glut4 in the GTN muscle measured using RT PCR. (n = 6). b Protein content of GLUT4 in the GTN muscle was measured as integrated intensity of the fluorescent bands (n = 7)
Fig. 4 Both mRNA and protein expression of the glucose transporter type 4 (Glut4/GLUT4) were decreased in the iMSBmal1 -/- mice. a mRNA expression of Glut4 in the GTN muscle measured using RT PCR. (n = 6). b Protein content of GLUT4 in the GTN muscle was measured as integrated intensity of the fluorescent bands (n = 7)CC BY · PubMed Central
Fig. 5 Activity of rate-limiting glycolytic enzymes (HK2 and PFK1) was significantly decreased in the iMSBmal1−/− mice. a mRNA expression of Hk2 obtained from microarray data (n = 6). b Enzymatic activity of the rate-limiting enzyme HK2 in the GTN muscle measured using a spectrophotometric assay (n = 7). c mRNA expression of the rate-limiting enzyme Pfkm in the GTN muscle (n = 7). d Enzymatic activity of PFKM in GTN muscles
Fig. 5 Activity of rate-limiting glycolytic enzymes (HK2 and PFK1) was significantly decreased in the iMSBmal1−/− mice. a mRNA expression of Hk2 obtained from microarray data (n = 6). b Enzymatic activity of the rate-limiting enzyme HK2 in the GTN muscle measured using a spectrophotometric assay (n = 7). c mRNA expression of the rate-limiting enzyme Pfkm in the GTN muscle (n = 7). d Enzymatic activity of PFKM in GTN musclesCC BY · PubMed Central
Fig. 6 Genes involved in fat metabolism are upregulated in the iMSBmal1−/− GTN. a Array data revealed that genes important in fat metabolism in the skeletal muscle are significantly upregulated in the iMSBmal1 −/− GTN. b Triglyceride levels trended toward a decrease in the iMSBmal1 −/− GTN
Fig. 6 Genes involved in fat metabolism are upregulated in the iMSBmal1−/− GTN. a Array data revealed that genes important in fat metabolism in the skeletal muscle are significantly upregulated in the iMSBmal1 −/− GTN. b Triglyceride levels trended toward a decrease in the iMSBmal1 −/− GTNCC BY · PubMed Central
Fig. 7 Summary of changes linked to substrate oxidation in the skeletal muscle. Metabolomics data, enzymatic activity data, glycogen data, and triglyceride data are included. Green upregulated, red downregulated, green italicized trending up, red italicized trending down, and black no change
Fig. 7 Summary of changes linked to substrate oxidation in the skeletal muscle. Metabolomics data, enzymatic activity data, glycogen data, and triglyceride data are included. Green upregulated, red downregulated, green italicized trending up, red italicized trending down, and black no changeCC BY · PubMed Central

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Metadata

Authors
Harfmann, B. D., Schroder, E. A., Kachman, M. T., Hodge, B. A., Zhang, X., & Esser, K. A.
Affiliations
  • University of Kentucky (US)
  • University of Michigan (US)
Corresponding author
Esser, Karyn A.
ORCID
Venue
Skeletal Muscle
Publisher
Springer Science and Business Media LLC
Published
2016-03-30
Volume
6
Issue
1
Pages
12-12
ISSN
2044-5040 (ISSN-L)
DOI
10.1186/s13395-016-0082-x
PMC
PMC4969979
OpenAlex
W2333878333
Cited by
231
References
38
Citations by year
2026: 24 · 2025: 30 · 2024: 24 · 2023: 20 · 2022: 29 · 2021: 19 · 2020: 33 · 2019: 17 · 2018: 15 · 2017: 18 · 2016: 2
FWCI
11.03
Type
journal article
Language
en
Open access
Licence
Locations
  • Skeletal Muscle (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • University of Florida Digital Collections (University of Florida) (submittedVersion, other-oa)
  • UKnowledge (University of Kentucky) (submittedVersion, cc-by)
Funders
National Institutes of Health (R01AR066082, RC1ES018636)
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
Keywords
Bmal1, circadian clock, glucose metabolism, glucose homeostasis, impaired glucose tolerance, hyperglycemia, insulin sensitivity, GLUT4, hexokinase 2, phosphofructokinase-1, glycolysis, TCA cycle, substrate metabolism, fat metabolism, protein degradation, body composition, diabetes mellitus
MeSH terms
Adipose Tissue, Aminoimidazole Carboxamide, Animals, Blood Glucose, Body Weight, Circadian Rhythm, Female, Hexokinase, Homeostasis, Hypoglycemic Agents, Insulin, Male, Motor Activity, Ribonucleotides, RNA, Messenger, Mice, Knockout, Muscle, Skeletal, Phosphofructokinase-1, Muscle Type, Glucose Transporter Type 4, Mice, ARNTL Transcription Factors

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