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Cited by 131Muscle Physiology and DisordersAdipose Tissue and MetabolismCardiovascular and exercise physiology

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Muscle-Specific Adaptations, Impaired Oxidative Capacity and Maintenance of Contractile Function Characterize Diet-Induced Obese Mouse Skeletal Muscle

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Shortreed, Karin E., Krause, Matthew P., Huang, Julianna H., Dhanani, Dili, Moradi, Jasmin, Ceddia, Rolando B., Hawke, Thomas J.·2009·PLoS ONE
DOI 10.1371/journal.pone.0007293PMC PMC2752162
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Abstract

BACKGROUND: The effects of diet-induced obesity on skeletal muscle function are largely unknown, particularly as it relates to changes in oxidative metabolism and morphology. PRINCIPAL FINDINGS: Compared to control fed mice, mice fed a high fat diet (HFD; 60% kcal: fat) for 8 weeks displayed increased body mass and insulin resistance without overt fasting hyperglycemia (i.e. pre-diabetic). Histological analysis revealed a greater oxidative potential in the HFD gastrocnemius/plantaris (increased IIA, reduced IIB fiber-type percentages) and soleus (increased I, IIA cross-sectional areas) muscles, but no change in fiber type percentages in tibialis anterior muscles compared to controls. Intramyocellular lipid levels were significantly increased relative to control in HFD gastrocnemius/plantaris, but were similar to control values in the HFD soleus. Using a novel, single muscle fiber approach, impairments in complete palmitate and glucose oxidation (72.8+/-6.6% and 61.8+/-9.1% of control, respectively; p<0.05) with HFD were detected. These reductions were consistent with measures made using intact extensor digitorum longus and soleus muscles. Compared to controls, no difference in succinate dehydrogenase or citrate synthase enzyme activities were observed between groups in any muscle studied, however, short-chain fatty acyl CoA dehydrogenase (SCHAD) activity was elevated in the HFD soleus, but not tibialis anterior muscles. Despite these morphological and metabolic alterations, no significant difference in peak tetanic force or low-frequency fatigue rates were observed between groups. CONCLUSIONS: These findings indicate that HFD induces early adaptive responses that occur in a muscle-specific pattern, but are insufficient to prevent impairments in oxidative metabolism with continued high-fat feeding. Moreover, the morphological and metabolic changes which occur with 8 weeks of HFD do not significantly impact muscle contractile properties.

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Figure 1 Eight weeks of a high fat diet (HFD) elicits pre-diabetes. (A) Fasted body mass was assessed before experimental diet began and after 4 and 8 weeks (N = 19 CON, 20 HFD). (B) Epididymal fat mass after 8 weeks of diet intervention (N = 19 CON, N = 20 HFD). (C) Intraperitoneal glucose tolerance test (IPGTT) performed after an overnight fast (16 hrs) 1 week before harvest (N = 19 CON, N = 18 HFD). (D) Plasma insulin levels assessed 4 weeks into diet intervention (8 hr fast, N = 10) and at IPGTT 45 minute time-point (16 hr fast, N = 4). Significance is represented by * vs. CON at same time point (A–D), a or b vs. 0 weeks within diet group, and c vs. 4 weeks within diet group, p<0.005.
Figure 1 Eight weeks of a high fat diet (HFD) elicits pre-diabetes. (A) Fasted body mass was assessed before experimental diet began and after 4 and 8 weeks (N = 19 CON, 20 HFD). (B) Epididymal fat mass after 8 weeks of diet intervention (N = 19 CON, N = 20 HFD). (C) Intraperitoneal glucose tolerance test (IPGTT) performed after an overnight fast (16 hrs) 1 week before harvest (N = 19 CON, N = 18 HFD). (D) Plasma insulin levels assessed 4 weeks into diet intervention (8 hr fast, N = 10) and at IPGTT 45 minute time-point (16 hr fast, N = 4). Significance is represented by * vs. CON at same time point (A–D), a or b vs. 0 weeks within diet group, and c vs. 4 weeks within diet group, p<0.005.CC BY · PubMed Central
Figure 2 Morphometric changes are muscle-specific. Serial cross-sections from control (CON, white bars in all graphs) and high fat diet (HFD, black bars in all graphs) fed mouse muscles [TA (top left only), gastrocnemius/plantaris complex (GP, all middle graphs), and soleus (all right graphs)] were examined for (A) fiber type composition, (B) area, (C) SDH stain intensity, and (D) IMCL stain intensity. Representative images of all stains used, performed on GP muscle cross-sections are shown to the left of graphs B–D with fiber type (type I, and types II- A, D, B) labeled with CON on the left and HFD on the right. (B) Metachromatic fiber type stain was used to assess fiber type. (C) SDH and (D) Oil-Red-O stains are graphically represented by arbitrary units (A.U.) of optical intensity measurements, with greater values for more intense stains and normalized to a percentage of all the control value means for each graph (% CON). All measurements were taken on an average of 51–331 total fibers/animal with a Nikon Eclipse 90i microscope (N = 3–4). Significance is represented by * vs. CON, p<0.005.
Figure 2 Morphometric changes are muscle-specific. Serial cross-sections from control (CON, white bars in all graphs) and high fat diet (HFD, black bars in all graphs) fed mouse muscles [TA (top left only), gastrocnemius/plantaris complex (GP, all middle graphs), and soleus (all right graphs)] were examined for (A) fiber type composition, (B) area, (C) SDH stain intensity, and (D) IMCL stain intensity. Representative images of all stains used, performed on GP muscle cross-sections are shown to the left of graphs B–D with fiber type (type I, and types II- A, D, B) labeled with CON on the left and HFD on the right. (B) Metachromatic fiber type stain was used to assess fiber type. (C) SDH and (D) Oil-Red-O stains are graphically represented by arbitrary units (A.U.) of optical intensity measurements, with greater values for more intense stains and normalized to a percentage of all the control value means for each graph (% CON). All measurements were taken on an average of 51–331 total fibers/animal with a Nikon Eclipse 90i microscope (N = 3–4). Significance is represented by * vs. CON, p<0.005.CC BY · PubMed Central
Figure 3 Impaired palmitate and glucose oxidation in HFD single fibers. (A) Palmitate (N = 19, average of 17 fibers/dish) and (B) glucose (N = 12 CON, N = 10 HFD, average of 23 fibers/dish) oxidation in single fibers derived from EDL and peroneus muscles was similarly impaired in mice fed a high-fat diet (HFD) compared to control (CON). Values were normalized to control values for each experiment and significance is represented by * vs. CON, p<0.005.
Figure 3 Impaired palmitate and glucose oxidation in HFD single fibers. (A) Palmitate (N = 19, average of 17 fibers/dish) and (B) glucose (N = 12 CON, N = 10 HFD, average of 23 fibers/dish) oxidation in single fibers derived from EDL and peroneus muscles was similarly impaired in mice fed a high-fat diet (HFD) compared to control (CON). Values were normalized to control values for each experiment and significance is represented by * vs. CON, p<0.005.CC BY · PubMed Central
Figure 4 Impaired oxidation, glycogen synthesis, and insulin stimulated response in HFD muscle. Palmitate oxidation in whole (A) EDL (N = 4) and (B) soleus (N = 4) muscles is impaired with HFD. Both glucose oxidation in whole (C) EDL and (D) soleus and glycogen synthesis in whole (E) EDL and (F) soleus muscles with HFD demonstrate a significant blunted response to insulin pre-incubation (INSULIN), vs. no insulin pre-incubation (BASAL), in HFD muscle (N = 4–6, two-way ANOVA with Bonferonni post-tests between insulin conditions within diet). Significance is represented by * vs. CON (A–B), and vs. INSULN (C–F), p<0.005.
Figure 4 Impaired oxidation, glycogen synthesis, and insulin stimulated response in HFD muscle. Palmitate oxidation in whole (A) EDL (N = 4) and (B) soleus (N = 4) muscles is impaired with HFD. Both glucose oxidation in whole (C) EDL and (D) soleus and glycogen synthesis in whole (E) EDL and (F) soleus muscles with HFD demonstrate a significant blunted response to insulin pre-incubation (INSULIN), vs. no insulin pre-incubation (BASAL), in HFD muscle (N = 4–6, two-way ANOVA with Bonferonni post-tests between insulin conditions within diet). Significance is represented by * vs. CON (A–B), and vs. INSULN (C–F), p<0.005.CC BY · PubMed Central
Figure 5 Oxidative enzyme alterations are muscle specific. Citrate synthase (CS) activity is unaltered in both (A) TA and (C) soleus muscle between control (CON) and high fat diet (HFD). Short chain 3-β-hydroxyacyl coenzyme-A dehydrogenase (SCHAD) activity is unaltered in (B) TA muscle, though (D) soleus muscle from HFD mice exhibits SCHAD activity 136% of CON. Significance is represented by * vs. CON, p<0.005.
Figure 5 Oxidative enzyme alterations are muscle specific. Citrate synthase (CS) activity is unaltered in both (A) TA and (C) soleus muscle between control (CON) and high fat diet (HFD). Short chain 3-β-hydroxyacyl coenzyme-A dehydrogenase (SCHAD) activity is unaltered in (B) TA muscle, though (D) soleus muscle from HFD mice exhibits SCHAD activity 136% of CON. Significance is represented by * vs. CON, p<0.005.CC BY · PubMed Central
Figure 6 In situ contractile analysis reveals trend towards force decrements, yet unaltered peak force and fatigue. Relative tetanic force production [in Newtons (N) per gram (g) of wet muscle mass] in the gastrocnemius/plantaris muscle group of high-fat diet (HFD) mice compared to control (CON) was (A) not different before (Pre) or after (Post) the fatigue protocol. (B) There was no difference between diets over all frequencies used to test force production pre-fatigue, however there was a significant main effect of diet post-fatigue. (C) Contractile force, relative to initial (% initial), throughout a 2 minute low-frequency fatigue protocol was not different between diet groups. Significance is represented by * vs. CON, p<0.005.
Figure 6 In situ contractile analysis reveals trend towards force decrements, yet unaltered peak force and fatigue. Relative tetanic force production [in Newtons (N) per gram (g) of wet muscle mass] in the gastrocnemius/plantaris muscle group of high-fat diet (HFD) mice compared to control (CON) was (A) not different before (Pre) or after (Post) the fatigue protocol. (B) There was no difference between diets over all frequencies used to test force production pre-fatigue, however there was a significant main effect of diet post-fatigue. (C) Contractile force, relative to initial (% initial), throughout a 2 minute low-frequency fatigue protocol was not different between diet groups. Significance is represented by * vs. CON, p<0.005.CC BY · PubMed Central

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Metadata

Authors
Shortreed, K. E., Krause, M. P., Huang, J. H., Dhanani, D., Moradi, J., Ceddia, R. B., & Hawke, T. J.
Affiliations
York University (CA)
Corresponding author
Hawke, Thomas J.
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2009-10-06
Volume
4
Issue
10
Pages
e7293
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0007293
PMC
PMC2752162
OpenAlex
W2116618150
Cited by
131
References
29
Citations by year
2026: 1 · 2025: 5 · 2024: 5 · 2023: 6 · 2022: 7 · 2021: 4 · 2020: 15 · 2019: 7 · 2018: 8 · 2017: 11 · 2016: 6 · 2015: 12 · 2014: 13 · 2013: 11 · 2012: 4
FWCI
2.66
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Ontario Innovation Trust
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
  • Health Sciences › Medicine › Physiology (medical) › Cardiovascular and exercise physiology
Keywords
diet-induced obesity, high-fat diet, skeletal muscle, oxidative metabolism, muscle fiber type, intramyocellular lipid, palmitate oxidation, glucose oxidation, succinate dehydrogenase, citrate synthase, muscle contractility, insulin resistance, prediabetes, gastrocnemius, soleus muscle, tibialis anterior, extensor digitorum longus
MeSH terms
Animals, Animal Feed, Blood Glucose, Dietary Fats, Glucose, Lipids, Male, Mice, Inbred C57BL, Muscle Contraction, Obesity, Oxygen, Time Factors, Muscle, Skeletal, Mice, Animal Nutrition Sciences

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