Letter to the Editor
Low macrophage content in diabetic and aging human skeletal muscle
Article first published online: 12 MAR 2013
Copyright © 2012 The Obesity Society
Volume 21, Issue 1, page 2, January 2013
How to Cite
Liu, D. and Gordon, P. M. (2013), Low macrophage content in diabetic and aging human skeletal muscle. Obesity, 21: 2. doi: 10.1002/oby.20006
- Issue published online: 12 MAR 2013
- Article first published online: 12 MAR 2013
- Accepted manuscript online: 7 AUG 2012 02:43PM EST
- Manuscript Accepted: 31 MAY 2012
TO THE EDITOR:
The prevailing viewpoint is that the accumulation of macrophages in adipose tissue plays a major role in obesity-associated inflammation.However, an increase in skeletal muscle macrophage content and subsequent paracrine effect has also been implicated in the pathogenesis of muscle insulin resistance (1, 2). Yet, other studies have found minimal amounts of macrophages in skeletal muscle and no relation to adiposity levels (3). The discrepancy in these findings may be due, in part, to different methods used for determining macrophage contents. For example, in obese human skeletal muscle, Varma et al. used immunohistochemistry staining for CD68 and found an increase in macrophage count (1); whereas, Bruun et al. used real-time polymerase chain reaction (RT-PCR) to measure CD68 mRNA levels and reported minimal macrophages that were unchanged following weight loss (3). To clarify the role of local macrophage in muscle insulin resistance in obesity and diabetes, studies using multiple methods to ascertain the quantity of macrophages are needed. A recent short communication by Tam et al. (4) represents such a study, in which both immunohistochemistry and gene expression were used to assess muscle macrophage content in obese diabetic and elderly individuals. Tam et al. reported little evidence of macrophage accumulation in muscle of obese diabetic (2–3%) or elderly (∼4%) individuals, based on immunohistochemistry staining for CD68. This was much lower than that observed by others who used similar methods and reported approximately 25% macrophages in the muscle of obese (1) and elderly (5) individuals. Tam et al. suggested that the reason for higher macrophage levels found by others might be due to contamination by adipose tissue, given that they observed greater CD68 staining in the intermuscular adipose tissue (IMAT) region of obese diabetic muscle. Tam et al. chose to exclude connective tissue and IMAT regions in the muscle sections used for macrophage counting, which we find concerning. Connective tissue and IMAT surrounding myofibers likely influence myofiber function. As suggested by Kewalramani et al., macrophages infiltrating muscle tissue, whether bordering the myofibers directly or surrounding muscle-infiltrating adipocytes, might have a large impact on muscle insulin activity (6). This notion is supported by in vitro studies, where conditioned medium collected from palmitic acid-treated macrophages resulted in a significant decrease in insulin-mediated glucose uptake in both cultured human muscle myotubes (1) and L6 myotubes (7).
Animal studies indicate that resident macrophages are extensively present in the connective tissue surrounding myofibers (8). Moreover, enlarged IMAT likely attracts monocyte-derived macrophages (9). Therefore, we feel that connective tissue and IMAT are important regions to examine for abnormalities in muscle macrophages. Excluding these compartments of muscle tissue could lead one to overlook the potential contribution of local macrophages to muscle metabolic dysfunction in obesity and aging.
Additionally, we are curious about the changes in macrophages following the exercise intervention in the diabetic patients. Although no significant change was reported, there appears to be an increase in macrophage content in at least half of the subjects based on the median and interquartile ranges at baseline 2.7 (2.0–3.2%) and postintervention 4.0 (3.2–6.8%).
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- 3Diet and exercise reduce low-grade inflammation and macrophage infiltration in adipose tissue but not in skeletal muscle in severely obese subjects. Am J Physiol Endocrinol Metab 2006; 290: E961–E967., , , .
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- 5Aging alters macrophage properties in human skeletal muscle both at rest and in response to acute resistance exercise. Exp Gerontol 2006; 41: 320–327., , , et al.
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- 7Palmitate-Activated Macrophages Confer Insulin Resistance to Muscle Cells by a Mechanism Involving Protein Kinase C theta and epsilon. PLoS One 2011; 6: e26947., , , .
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Dongmei Liu*, Paul M. Gordon*, * Laboratory for Physical Activity and Exercise Intervention Research (PAEIR), Department of Physical Medicine and Rehabilitation, University of Michigan, Ann Arbor, Michigan, USA.