Diabetes Metab J.  2021 Jul;45(4):482-491. 10.4093/dmj.2020.0277.

Computed Tomography-Derived Myosteatosis and Metabolic Disorders

• Miljkovic I
• Vella CA
• Allison M

• KMID: 2518890
• DOI: http://doi.org/10.4093/dmj.2020.0277

Abstract

The role of ectopic adipose tissue infiltration into skeletal muscle (i.e., myosteatosis) for metabolic disorders has received considerable and increasing attention in the last 10 years. The purpose of this review was to evaluate and summarize existing studies focusing on computed tomography (CT)-derived measures of myosteatosis and metabolic disorders. There is consistent evidence that CT-derived myosteatosis contributes to dysglycemia, insulin resistance, type 2 diabetes mellitus, and inflammation, and, to some extent, dyslipidemia, independent of general obesity, visceral fat, and other relevant risk factors, suggesting that it may serve as a tool for metabolic risk prediction. Identification of which muscles should be examined, and the standardized CT protocols to be employed, are necessary to enhance the applicability of findings from epidemiologic studies of myosteatosis. Additional and longer longitudinal studies are necessary to confirm a role of myosteatosis in the development of type 2 diabetes mellitus, and examine these associations in a variety of muscles across multiple race/ethnic populations. Given the emerging role of myosteatosis in metabolic health, well-designed intervention studies are needed to investigate relevant lifestyle and pharmaceutical approaches.

Keyword

Adipose tissue; Diabetes mellitus, type 2; Dyslipidemias; Inflammation; Insulin resistance; Muscle, skeletal

Figure

• 

  Fig. 1. Representation of areas of interest (adipose tissue and muscle measures) derived from abdominal computed tomography (CT) scans in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort. The morphologically discrete tissues measured during CT image processing are: subcutaneous area which lies between the dermis and the fascia of the abdominal muscles; visceral cavity area with the internal organs; and abdominal skeletal muscles. The specific muscle groups denoted by psoas muscles (yellow arrows), paraspinal muscles (green arrows), oblique muscles (red arrows), and rectus abdominis muscles (blue arrows). Adipose tissue is identified as being between –190 and –30 Hounsfield units (HU). Lean tissue is identified as being between 0 and 100 HU. Inter-muscular adipose tissue is the sum of the pixels within a given muscle fascia. Intramuscular fat is computed as the mean of the pixel HU values between 0 and 99 for a given muscle group, with a higher mean density value for muscle indicating less intramuscular fat.

• 

  Fig. 2. Potential mechanisms underlying metabolic consequences of computed tomography-derived myosteatosis.

• 

Reference

1. Carobbio S, Rodriguez-Cuenca S, Vidal-Puig A. Origins of metabolic complications in obesity: ectopic fat accumulation. The importance of the qualitative aspect of lipotoxicity. Curr Opin Clin Nutr Metab Care. 2011; 14:520–6.

2. Morelli M, Gaggini M, Daniele G, Marraccini P, Sicari R, Gastaldelli A. Ectopic fat: the true culprit linking obesity and cardiovascular disease? Thromb Haemost. 2013; 110:651–60.

3. Rutkowski JM, Stern JH, Scherer PE. The cell biology of fat expansion. J Cell Biol. 2015; 208:501–12.

4. Correa-de-Araujo R, Harris-Love MO, Miljkovic I, Fragala MS, Anthony BW, Manini TM. The need for standardized assessment of muscle quality in skeletal muscle function deficit and other aging-related muscle dysfunctions: a symposium report. Front Physiol. 2017; 8:87.

5. Correa-de-Araujo R, Addison O, Miljkovic I, Goodpaster BH, Bergman BC, Clark RV, et al. Myosteatosis in the context of skeletal muscle function deficit: an interdisciplinary workshop at the national institute on aging. Front Physiol. 2020; 11:963.

6. Kelley DE, Slasky BS, Janosky J. Skeletal muscle density: effects of obesity and non-insulin-dependent diabetes mellitus. Am J Clin Nutr. 1991; 54:509–15.

7. Aubrey J, Esfandiari N, Baracos VE, Buteau FA, Frenette J, Putman CT, et al. Measurement of skeletal muscle radiation attenuation and basis of its biological variation. Acta Physiol (Oxf). 2014; 210:489–97.

8. Vettor R, Milan G, Franzin C, Sanna M, De Coppi P, Rizzuto R, et al. The origin of intermuscular adipose tissue and its pathophysiological implications. Am J Physiol Endocrinol Metab. 2009; 297:E987–98.

9. Miljkovic I, Zmuda JM. Epidemiology of myosteatosis. Curr Opin Clin Nutr Metab Care. 2010; 13:260–4.

10. Goodpaster BH, Kelley DE, Thaete FL, He J, Ross R. Skeletal muscle attenuation determined by computed tomography is associated with skeletal muscle lipid content. J Appl Physiol (1985). 2000; 89:104–10.

11. Trayhurn P, Drevon CA, Eckel J. Secreted proteins from adipose tissue and skeletal muscle: adipokines, myokines and adipose/muscle cross-talk. Arch Physiol Biochem. 2011; 117:47–56.

12. Samuel VT, Shulman GI. The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux. J Clin Invest. 2016; 126:12–22.

13. Goodpaster BH, Krishnaswami S, Resnick H, Kelley DE, Haggerty C, Harris TB, et al. Association between regional adipose tissue distribution and both type 2 diabetes and impaired glucose tolerance in elderly men and women. Diabetes Care. 2003; 26:372–9.

14. Kim D, Nam S, Ahn C, Kim K, Yoon S, Kim J, et al. Correlation between midthigh low-density muscle and insulin resistance in obese nondiabetic patients in Korea. Diabetes Care. 2003; 26:1825–30.

15. Miljkovic-Gacic I, Gordon CL, Goodpaster BH, Bunker CH, Patrick AL, Kuller LH, et al. Adipose tissue infiltration in skeletal muscle: age patterns and association with diabetes among men of African ancestry. Am J Clin Nutr. 2008; 87:1590–5.

16. Elbein SC, Rasouli N. Intermuscular lipid: a marker of disordered fat partitioning or the consequence of obesity? Am J Clin Nutr. 2008; 87:1585–6.

17. Miljkovic I, Cauley JA, Wang PY, Holton KF, Lee CG, Sheu Y, et al. Abdominal myosteatosis is independently associated with hyperinsulinemia and insulin resistance among older men without diabetes. Obesity (Silver Spring). 2013; 21:2118–25.

18. Granados A, Gebremariam A, Gidding SS, Terry JG, Carr JJ, Steffen LM, et al. Association of abdominal muscle composition with prediabetes and diabetes: the CARDIA study. Diabetes Obes Metab. 2019; 21:267–75.

19. Therkelsen KE, Pedley A, Speliotes EK, Massaro JM, Murabito J, Hoffmann U, et al. Intramuscular fat and associations with metabolic risk factors in the Framingham Heart Study. Arterioscler Thromb Vasc Biol. 2013; 33:863–70.

20. Miljkovic I, Kuipers AL, Cvejkus RK, Carr JJ, Terry JG, Thyagarajan B, et al. Hepatic and skeletal muscle adiposity are associated with diabetes independent of visceral adiposity in nonobese African-Caribbean men. Metab Syndr Relat Disord. 2020; 18:275–83.

21. George AM, Jacob AG, Fogelfeld L. Lean diabetes mellitus: an emerging entity in the era of obesity. World J Diabetes. 2015; 6:613–20.

22. Flowers E, Lin F, Kandula NR, Allison M, Carr JJ, Ding J, et al. Body composition and diabetes risk in South Asians: findings from the MASALA and MESA studies. Diabetes Care. 2019; 42:946–53.

23. Miljkovic I, Kuipers AL, Cvejkus R, Bunker CH, Patrick AL, Gordon CL, et al. Myosteatosis increases with aging and is associated with incident diabetes in African ancestry men. Obesity (Silver Spring). 2016; 24:476–82.

24. Tanaka M, Okada H, Hashimoto Y, Kumagai M, Nishimura H, Fukui M. Low-attenuation muscle is a predictor of diabetes mellitus: a population-based cohort study. Nutrition. 2020; 74:110752.

25. Camastra S, Vitali A, Anselmino M, Gastaldelli A, Bellini R, Berta R, et al. Muscle and adipose tissue morphology, insulin sensitivity and beta-cell function in diabetic and nondiabetic obese patients: effects of bariatric surgery. Sci Rep. 2017; 7:9007.

26. Ferrannini E, Iozzo P, Virtanen KA, Honka MJ, Bucci M, Nuutila P. Adipose tissue and skeletal muscle insulin-mediated glucose uptake in insulin resistance: role of blood flow and diabetes. Am J Clin Nutr. 2018; 108:749–58.

27. Pasarica M, Sereda OR, Redman LM, Albarado DC, Hymel DT, Roan LE, et al. Reduced adipose tissue oxygenation in human obesity: evidence for rarefaction, macrophage chemotaxis, and inflammation without an angiogenic response. Diabetes. 2009; 58:718–25.

28. Lee DE, Kehlenbrink S, Lee H, Hawkins M, Yudkin JS. Getting the message across: mechanisms of physiological cross talk by adipose tissue. Am J Physiol Endocrinol Metab. 2009; 296:E1210–29.

29. Gavin TP, Stallings HW 3rd, Zwetsloot KA, Westerkamp LM, Ryan NA, Moore RA, et al. Lower capillary density but no difference in VEGF expression in obese vs. lean young skeletal muscle in humans. J Appl Physiol (1985). 2005; 98:315–21.

30. Sorop O, Olver TD, van de Wouw J, Heinonen I, van Duin RW, Duncker DJ, et al. The microcirculation: a key player in obesity-associated cardiovascular disease. Cardiovasc Res. 2017; 113:1035–45.

31. Ahima RS, Park HK. Connecting myokines and metabolism. Endocrinol Metab (Seoul). 2015; 30:235–45.

32. Sachs S, Zarini S, Kahn DE, Harrison KA, Perreault L, Phang T, et al. Intermuscular adipose tissue directly modulates skeletal muscle insulin sensitivity in humans. Am J Physiol Endocrinol Metab. 2019; 316:E866–79.

33. Konopka AR, Wolff CA, Suer MK, Harber MP. Relationship between intermuscular adipose tissue infiltration and myostatin before and after aerobic exercise training. Am J Physiol Regul Integr Comp Physiol. 2018; 315:R461–8.

34. Miljkovic I, Kuipers AL, Kuller LH, Sheu Y, Bunker CH, Patrick AL, et al. Skeletal muscle adiposity is associated with serum lipid and lipoprotein levels in Afro-Caribbean men. Obesity (Silver Spring). 2013; 21:1900–7.

35. Durheim MT, Slentz CA, Bateman LA, Mabe SK, Kraus WE. Relationships between exercise-induced reductions in thigh intermuscular adipose tissue, changes in lipoprotein particle size, and visceral adiposity. Am J Physiol Endocrinol Metab. 2008; 295:E407–12.

36. Vella CA, Nelson MC, Unkart JT, Miljkovic I, Allison MA. Skeletal muscle area and density are associated with lipid and lipoprotein cholesterol levels: the Multi-Ethnic Study of Atherosclerosis. J Clin Lipidol. 2020; 14:143–53.

37. Mesinovic J, McMillan LB, Shore-Lorenti C, De Courten B, Ebeling PR, Scott D. Metabolic syndrome and its associations with components of sarcopenia in overweight and obese older adults. J Clin Med. 2019; 8:145.

38. Miljkovic I, Kuipers AL, Kammerer CM, Wang X, Bunker CH, Patrick AL, et al. Markers of inflammation are heritable and associated with subcutaneous and ectopic skeletal muscle adiposity in African ancestry families. Metab Syndr Relat Disord. 2011; 9:319–26.

39. Van Hollebeke RB, Cushman M, Schlueter EF, Allison MA. Abdominal muscle density is inversely related to adiposity inflammatory mediators. Med Sci Sports Exerc. 2018; 50:1495–501.

40. Vella CA, Cushman M, Van Hollebeke RB, Allison MA. Associations of abdominal muscle area and radiodensity with adiponectin and leptin: the Multiethnic Study of Atherosclerosis. Obesity (Silver Spring). 2018; 26:1234–41.

41. Vella CA, Allison MA. Associations of abdominal intermuscular adipose tissue and inflammation: the Multi-Ethnic Study of Atherosclerosis. Obes Res Clin Pract. 2018; 12:534–40.

42. Beasley LE, Koster A, Newman AB, Javaid MK, Ferrucci L, Kritchevsky SB, et al. Inflammation and race and gender differences in computerized tomography-measured adipose depots. Obesity (Silver Spring). 2009; 17:1062–9.

43. Anderson DE, D’Agostino JM, Bruno AG, Demissie S, Kiel DP, Bouxsein ML. Variations of CT-based trunk muscle attenuation by age, sex, and specific muscle. J Gerontol A Biol Sci Med Sci. 2013; 68:317–23.

44. Xiao J, Caan BJ, Weltzien E, Cespedes Feliciano EM, Kroenke CH, Meyerhardt JA, et al. Associations of pre-existing co-morbidities with skeletal muscle mass and radiodensity in patients with non-metastatic colorectal cancer. J Cachexia Sarcopenia Muscle. 2018; 9:654–63.

45. Goodpaster BH, Carlson CL, Visser M, Kelley DE, Scherzinger A, Harris TB, et al. Attenuation of skeletal muscle and strength in the elderly: the Health ABC Study. J Appl Physiol (1985). 2001; 90:2157–65.

46. Hicks GE, Simonsick EM, Harris TB, Newman AB, Weiner DK, Nevitt MA, et al. Trunk muscle composition as a predictor of reduced functional capacity in the health, aging and body composition study: the moderating role of back pain. J Gerontol A Biol Sci Med Sci. 2005; 60:1420–4.

47. Ryan AS, Buscemi A, Forrester L, Hafer-Macko CE, Ivey FM. Atrophy and intramuscular fat in specific muscles of the thigh: associated weakness and hyperinsulinemia in stroke survivors. Neurorehabil Neural Repair. 2011; 25:865–72.

48. Gallagher D, Kuznia P, Heshka S, Albu J, Heymsfield SB, Goodpaster B, et al. Adipose tissue in muscle: a novel depot similar in size to visceral adipose tissue. Am J Clin Nutr. 2005; 81:903–10.

49. Miljkovic I, Cauley JA, Petit MA, Ensrud KE, Strotmeyer E, Sheu Y, et al. Greater adipose tissue infiltration in skeletal muscle among older men of African ancestry. J Clin Endocrinol Metab. 2009; 94:2735–42.

50. Delmonico MJ, Harris TB, Visser M, Park SW, Conroy MB, Velasquez-Mieyer P, et al. Longitudinal study of muscle strength, quality, and adipose tissue infiltration. Am J Clin Nutr. 2009; 90:1579–85.

51. Eastwood SV, Tillin T, Wright A, Mayet J, Godsland I, Forouhi NG, et al. Thigh fat and muscle each contribute to excess cardiometabolic risk in South Asians, independent of visceral adipose tissue. Obesity (Silver Spring). 2014; 22:2071–9.

52. Vella CA, Michos ED, Sears DD, Cushman M, Van Hollebeke RB, Wiest MM, et al. Associations of sedentary behavior and abdominal muscle density: the Multi-Ethnic Study of Atherosclerosis. J Phys Act Health. 2018; 15:827–33.

53. Crawford MA, Criqui MH, Forbang N, Unkart JT, Allison MA, Larsen BA. Associations of abdominal muscle area and density with coronary artery calcium volume and density: the multiethnic study of atherosclerosis. Metabolism. 2020; 107:154230.

54. Larsen B, Bellettiere J, Allison M, McClelland RL, Miljkovic I, Vella CA, et al. Muscle area and density and risk of all-cause mortality: the Multi-Ethnic Study of Atherosclerosis. Metabolism. 2020; 111:154321.

55. Taaffe DR, Henwood TR, Nalls MA, Walker DG, Lang TF, Harris TB. Alterations in muscle attenuation following detraining and retraining in resistance-trained older adults. Gerontology. 2009; 55:217–23.

56. Prior SJ, Joseph LJ, Brandauer J, Katzel LI, Hagberg JM, Ryan AS. Reduction in midthigh low-density muscle with aerobic exercise training and weight loss impacts glucose tolerance in older men. J Clin Endocrinol Metab. 2007; 92:880–6.

57. Manini TM, Clark BC, Nalls MA, Goodpaster BH, PloutzSnyder LL, Harris TB. Reduced physical activity increases intermuscular adipose tissue in healthy young adults. Am J Clin Nutr. 2007; 85:377–84.

58. Goodpaster BH, Chomentowski P, Ward BK, Rossi A, Glynn NW, Delmonico MJ, et al. Effects of physical activity on strength and skeletal muscle fat infiltration in older adults: a randomized controlled trial. J Appl Physiol (1985). 2008; 105:1498–503.