Skeletal muscle fibrosis is associated with decreased muscle inflammation and weakness in patients with chronic kidney disease

被引:47
作者
Abramowitz, Matthew K. [1 ]
Paredes, William [1 ]
Zhang, Kehao [1 ]
Brightwell, Camille R. [2 ]
Newsom, Julia N. [2 ]
Kwon, Hyok-Joon [3 ]
Custodio, Matthew [1 ]
Buttar, Rupinder S. [1 ]
Farooq, Hina [1 ]
Zaidi, Bushra [1 ]
Pai, Rima [1 ]
Pessin, Jeffrey E. [1 ,4 ]
Hawkins, Meredith [1 ]
Fry, E. Christopher S. [2 ]
机构
[1] Albert Einstein Coll Med, Dept Med, Bronx, NY 10467 USA
[2] Univ Texas Med Branch, Dept Nutr & Metab, Galveston, TX 77555 USA
[3] Rutgers State Univ, Robert Wood Johnson Med Sch, Dept Med, New Brunswick, NJ USA
[4] Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10467 USA
关键词
chronic kidney disease; fibrosis; inflammation; skeletal muscle; STAGE RENAL-DISEASE; EXTRACELLULAR-MATRIX; PHYSICAL-ACTIVITY; UNITED-STATES; MECHANICAL-PROPERTIES; FORCE TRANSMISSION; CONNECTIVE-TISSUE; SATELLITE CELL; DIALYSIS; HEMODIALYSIS;
D O I
10.1152/ajprenal.00314.2018
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
Muscle dysfunction is an important cause of morbidity among patients with chronic kidney disease (CKD). Although muscle fibrosis is present in a CKD rodent model, its existence in humans and its impact on physical function are currently unknown. We examined isometric lee extension strength and measures of skeletal muscle fibrosis and inflammation in vastus lateralis muscle from CKD patients (n = 10) and healthy, sedentary controls (n = 10). Histochemistry and immunohistochemistry were used to assess muscle collagen and macrophage and fibro/adipogenic progenitor (FAP) cell populations. and RT-qPCR was used to assess muscle-specific inflammatory marker expression. Muscle collagen content was significantly greater in CKD compared with control (18.8 +/- 2.1 vs. 11.7 +/- 0.7% collagen area, P = 0.008), as was staining for collagen I, pro-collagen I, and a novel collagen-hybridizing peptide that binds remodeling collagen. Muscle collagen was inversely associated with leg extension strength in CKD (r = -0.74. P = 0.01). FAP abundance was increased in CKD, was highly correlated with muscle collagen (r = 0.84, P < 0.001). and was inversely associated with TNF-alpha expression (r = -0.65, P = 0.003). TNF-alpha, CD68, CCL2, and CCL5 mRNA were significantly lower in CKD than control, despite higher serum TNF-alpha and IL-6. Immunohistochemistry confirmed fewer CD68+ and CD11b+ macrophages in CKD muscle. In conclusion, skeletal muscle collagen content is increased in humans with CKD and is associated with functional parameters. Muscle fibrosis correlated with increased FAP abundance, which may be due to insufficient macrophage-mediated TNF-alpha secretion. These data provide a foundation for future research elucidating the mechanisms responsible for this newly identified human muscle pathology.
引用
收藏
页码:F1658 / F1669
页数:12
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