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Skeletal muscle mitochondria in insulin resistance: differences in intermyofibrillar versus subsarcolemmal subpopulations and relationship to metabolic flexibility.
J Clin Endocrinol Metab 2011; 96(2):494-503JC

Abstract

CONTEXT

Insulin resistance is accompanied by lower lipid oxidation during fasting and metabolic inflexibility. Whether these abnormalities correlate with mitochondrial content in skeletal muscle is unknown.

OBJECTIVE

The objective of the study was to investigate whether decreased fasting lipid oxidation, metabolic inflexibility, and impaired glucose disposal correlate with reduced mitochondrial content in intermyofibrillar vs. subsarcolemmal (SS) subpopulations.

DESIGN

Forty sedentary adults with a wide spectrum of insulin sensitivity were studied: insulin-sensitive lean subjects, insulin-resistant nondiabetic subjects, and subjects with type 2 diabetes mellitus. Glucose disposal was measured by euglycemic clamp and [6,6-D(2)]-glucose methodology. Fuel oxidation and metabolic flexibility (during clamps) were assessed by indirect calorimetry. Maximum aerobic capacity was assessed by treadmill testing. Intermyofibrillar and SS mitochondrial content were measured by quantitative electron microscopy of muscle biopsy samples.

RESULTS

Intermyofibrillar mitochondrial content was lower in the insulin-resistant nondiabetic subjects and type 2 diabetes mellitus groups, significantly correlating with glucose disposal in both men (R = 0.72, P < 0.01) and women (R = 0.53, P < 0.01). In contrast, SS mitochondrial content was similar among groups. Lower intermyofibrillar mitochondrial content was not explained by mitochondrial size, altered fiber-type distribution, or differences in maximum aerobic capacity. Intermyofibrillar mitochondrial content was significantly correlated with fasting respiratory quotient (R = -0.46, P = 0.003) and metabolic flexibility (R = 0.38, P = 0.02).

CONCLUSIONS

In obese-insulin-resistant subjects with or without diabetes, intermyofibrillar mitochondrial content is decreased. This is not entirely explained by fitness status or fiber-type composition. SS mitochondrial content is unaffected, suggesting independent mitochondrial pool regulation. Lower mitochondrial content correlates with lower fasting lipid oxidation and metabolic inflexibility, suggesting it may be intrinsically linked to abnormal fuel utilization patterns of obesity-associated insulin resistance.

Authors+Show Affiliations

Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

21106709

Citation

Chomentowski, Peter, et al. "Skeletal Muscle Mitochondria in Insulin Resistance: Differences in Intermyofibrillar Versus Subsarcolemmal Subpopulations and Relationship to Metabolic Flexibility." The Journal of Clinical Endocrinology and Metabolism, vol. 96, no. 2, 2011, pp. 494-503.
Chomentowski P, Coen PM, Radiková Z, et al. Skeletal muscle mitochondria in insulin resistance: differences in intermyofibrillar versus subsarcolemmal subpopulations and relationship to metabolic flexibility. J Clin Endocrinol Metab. 2011;96(2):494-503.
Chomentowski, P., Coen, P. M., Radiková, Z., Goodpaster, B. H., & Toledo, F. G. (2011). Skeletal muscle mitochondria in insulin resistance: differences in intermyofibrillar versus subsarcolemmal subpopulations and relationship to metabolic flexibility. The Journal of Clinical Endocrinology and Metabolism, 96(2), pp. 494-503. doi:10.1210/jc.2010-0822.
Chomentowski P, et al. Skeletal Muscle Mitochondria in Insulin Resistance: Differences in Intermyofibrillar Versus Subsarcolemmal Subpopulations and Relationship to Metabolic Flexibility. J Clin Endocrinol Metab. 2011;96(2):494-503. PubMed PMID: 21106709.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Skeletal muscle mitochondria in insulin resistance: differences in intermyofibrillar versus subsarcolemmal subpopulations and relationship to metabolic flexibility. AU - Chomentowski,Peter, AU - Coen,Paul M, AU - Radiková,Zofia, AU - Goodpaster,Bret H, AU - Toledo,Frederico G S, Y1 - 2010/11/24/ PY - 2010/11/26/entrez PY - 2010/11/26/pubmed PY - 2011/3/22/medline SP - 494 EP - 503 JF - The Journal of clinical endocrinology and metabolism JO - J. Clin. Endocrinol. Metab. VL - 96 IS - 2 N2 - CONTEXT: Insulin resistance is accompanied by lower lipid oxidation during fasting and metabolic inflexibility. Whether these abnormalities correlate with mitochondrial content in skeletal muscle is unknown. OBJECTIVE: The objective of the study was to investigate whether decreased fasting lipid oxidation, metabolic inflexibility, and impaired glucose disposal correlate with reduced mitochondrial content in intermyofibrillar vs. subsarcolemmal (SS) subpopulations. DESIGN: Forty sedentary adults with a wide spectrum of insulin sensitivity were studied: insulin-sensitive lean subjects, insulin-resistant nondiabetic subjects, and subjects with type 2 diabetes mellitus. Glucose disposal was measured by euglycemic clamp and [6,6-D(2)]-glucose methodology. Fuel oxidation and metabolic flexibility (during clamps) were assessed by indirect calorimetry. Maximum aerobic capacity was assessed by treadmill testing. Intermyofibrillar and SS mitochondrial content were measured by quantitative electron microscopy of muscle biopsy samples. RESULTS: Intermyofibrillar mitochondrial content was lower in the insulin-resistant nondiabetic subjects and type 2 diabetes mellitus groups, significantly correlating with glucose disposal in both men (R = 0.72, P < 0.01) and women (R = 0.53, P < 0.01). In contrast, SS mitochondrial content was similar among groups. Lower intermyofibrillar mitochondrial content was not explained by mitochondrial size, altered fiber-type distribution, or differences in maximum aerobic capacity. Intermyofibrillar mitochondrial content was significantly correlated with fasting respiratory quotient (R = -0.46, P = 0.003) and metabolic flexibility (R = 0.38, P = 0.02). CONCLUSIONS: In obese-insulin-resistant subjects with or without diabetes, intermyofibrillar mitochondrial content is decreased. This is not entirely explained by fitness status or fiber-type composition. SS mitochondrial content is unaffected, suggesting independent mitochondrial pool regulation. Lower mitochondrial content correlates with lower fasting lipid oxidation and metabolic inflexibility, suggesting it may be intrinsically linked to abnormal fuel utilization patterns of obesity-associated insulin resistance. SN - 1945-7197 UR - https://www.unboundmedicine.com/medline/citation/21106709/Skeletal_muscle_mitochondria_in_insulin_resistance:_differences_in_intermyofibrillar_versus_subsarcolemmal_subpopulations_and_relationship_to_metabolic_flexibility_ L2 - https://academic.oup.com/jcem/article-lookup/doi/10.1210/jc.2010-0822 DB - PRIME DP - Unbound Medicine ER -