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

Matthew K. Abramowitz, William Paredes, Kehao Zhang, Camille R. Brightwell, Julia N. Newsom, Hyok Joon Kwon, Matthew Custodio, Rupinder S. Buttar, Hina Farooq, Bushra Zaidi, Rima Pai, Jeffrey E. Pessin, Meredith Hawkins, Christopher Fry

Research output: Contribution to journalArticle

Abstract

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 leg 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-_ expression (r=_0.65, P = 0.003). TNF-α, CD68, CCL2, and CCL5 mRNA were significantly lower in CKD than control, despite higher serum TNF- α 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- α secretion. These data provide a foundation for future research elucidating the mechanisms responsible for this newly identified human muscle pathology.

Original languageEnglish (US)
Pages (from-to)F1658-F1669
JournalAmerican Journal of Physiology - Renal Physiology
Volume315
Issue number6
DOIs
StatePublished - Dec 4 2018

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Muscle Weakness
Chronic Renal Insufficiency
Skeletal Muscle
Fibrosis
Collagen
Inflammation
Muscles
Macrophages
Leg
Immunohistochemistry
Quadriceps Muscle
Rodentia
Interleukin-6
Stem Cells
Pathology
Staining and Labeling
Morbidity
Messenger RNA
Peptides

ASJC Scopus subject areas

  • Physiology
  • Urology

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Skeletal muscle fibrosis is associated with decreased muscle inflammation and weakness in patients with chronic kidney disease. / Abramowitz, Matthew K.; Paredes, William; Zhang, Kehao; Brightwell, Camille R.; Newsom, Julia N.; Kwon, Hyok Joon; Custodio, Matthew; Buttar, Rupinder S.; Farooq, Hina; Zaidi, Bushra; Pai, Rima; Pessin, Jeffrey E.; Hawkins, Meredith; Fry, Christopher.

In: American Journal of Physiology - Renal Physiology, Vol. 315, No. 6, 04.12.2018, p. F1658-F1669.

Research output: Contribution to journalArticle

Abramowitz, MK, Paredes, W, Zhang, K, Brightwell, CR, Newsom, JN, Kwon, HJ, Custodio, M, Buttar, RS, Farooq, H, Zaidi, B, Pai, R, Pessin, JE, Hawkins, M & Fry, C 2018, 'Skeletal muscle fibrosis is associated with decreased muscle inflammation and weakness in patients with chronic kidney disease', American Journal of Physiology - Renal Physiology, vol. 315, no. 6, pp. F1658-F1669. https://doi.org/10.1152/ajprenal.00314.2018
Abramowitz, Matthew K. ; Paredes, William ; Zhang, Kehao ; Brightwell, Camille R. ; Newsom, Julia N. ; Kwon, Hyok Joon ; Custodio, Matthew ; Buttar, Rupinder S. ; Farooq, Hina ; Zaidi, Bushra ; Pai, Rima ; Pessin, Jeffrey E. ; Hawkins, Meredith ; Fry, Christopher. / Skeletal muscle fibrosis is associated with decreased muscle inflammation and weakness in patients with chronic kidney disease. In: American Journal of Physiology - Renal Physiology. 2018 ; Vol. 315, No. 6. pp. F1658-F1669.
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AU - Paredes, William

AU - Zhang, Kehao

AU - Brightwell, Camille R.

AU - Newsom, Julia N.

AU - Kwon, Hyok Joon

AU - Custodio, Matthew

AU - Buttar, Rupinder S.

AU - Farooq, Hina

AU - Zaidi, Bushra

AU - Pai, Rima

AU - Pessin, Jeffrey E.

AU - Hawkins, Meredith

AU - Fry, Christopher

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N2 - 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 leg 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-_ expression (r=_0.65, P = 0.003). TNF-α, CD68, CCL2, and CCL5 mRNA were significantly lower in CKD than control, despite higher serum TNF- α 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- α secretion. These data provide a foundation for future research elucidating the mechanisms responsible for this newly identified human muscle pathology.

AB - 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 leg 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-_ expression (r=_0.65, P = 0.003). TNF-α, CD68, CCL2, and CCL5 mRNA were significantly lower in CKD than control, despite higher serum TNF- α 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- α secretion. These data provide a foundation for future research elucidating the mechanisms responsible for this newly identified human muscle pathology.

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