Response to low macrophage content in diabetic and aging human skeletal muscle

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  • Disclosure: The authors declared no conflict of interest.

TO THE EDITOR:

The pro-inflammatory role of macrophage accumulation in white adipose tissue in obesity is well established and may be one of the causes of insulin resistance. Whether macrophage accumulation in skeletal muscle further contributes to the inflammatory state and insulin resistance is less clear. We, therefore, measured inflammation gene expression and CD68+ macrophages in skeletal muscle from obese subjects with type 2 diabetes mellitus before and after a 9-month exercise intervention (1). In contrast to previous studies in similarly obese subjects (2, 3), we found relatively few macrophages (2-3%) and low inflammation gene expression (CD68, CCL2, CD40, CD206, CD11c, Arginase 1) in obese skeletal muscle, which was unchanged after exercise training (1).

We examined skeletal muscle sections, deliberately excluding areas of connective tissue and adjacent adipose tissue, and concluded that greater macrophage accumulation in other studies may potentially be due to contamination with adipose tissue. In response to our report (1), Liu and Gordon pointed out that connective tissue and inter-muscular adipose tissue (IMAT) may be important regions to examine macrophages in skeletal muscle (4). Indeed, recent studies in subcutaneous and omental adipose tissue in obese humans have demonstrated that connective tissue regions (fibrotic areas within adipose tissue) contain macrophages (M1 and M2 phenotype) and mast cells, with few T lymphocytes (5). Spencer et al. found higher macrophage accumulation in fibrotic areas in obese compared to lean subjects (6).

Together, these studies indicate potential cross-talks between inflammatory cells in fibrotic areas and the adipocyte, which may further exacerbate obesity-associated low grade inflammation and potential insulin resistance (5, 6). As pointed out (4), it is possible that immune cells may also be present in connective tissue areas in skeletal muscle, as shown in rodents (7) but yet not in humans. Interestingly, when we re-examined our skeletal muscle sections, we saw few to no areas of connective tissue (data not shown).

Liu and Gordon also suggest that macrophages may be present in IMAT which is located between muscle bundles and clearly separated from subcutaneous adipose tissue (8). Magnetic resonance imaging studies demonstrate that such fat depots are approximately twofold higher in subjects with obesity and type 2 diabetes (8). Furthermore, in vitro co-culturing of human myotubes and adipocytes results in impaired insulin action depending on the metabolic state of the system (9). Unfortunately, IMAT depots are difficult if not impossible to obtain from muscle biopsies. In addition, in response to the authors' comments, we re-examined the raw data and noted that 5 out of the 7 subjects had relatively small increases in macrophage accumulation after exercise training.

In summary, there is a need for further investigations examining inflammation in skeletal muscle in the context of obesity and type 2 diabetes and its potential role in mediating insulin resistance. In vitro studies using palmitate treated macrophages have demonstrated impaired insulin-mediated glucose uptake in cultured human (2) and L6 myotubes (10). Exploring immune cells in areas of connective tissue and adjacent adipose tissue clusters in skeletal muscle from obese subjects may provide further insights into muscle inflammation.

Charmaine S. Tam* †, Jeffrey D. Covington*, Eric Ravussin*, * Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA, † The Charles Perkins Centre and School of Biological Sciences, University of Sydney, NSW, Australia

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