Skeletal muscle fibrosis is associated with decreased muscle inflammation and weakness in patients with chronic kidney disease
Chronic kidney disease (CKD) progressively impairs kidney function, affecting millions. Beyond kidney-related complications, patients often experience muscle weakness and reduced mobility, begging the question: does muscle fibrosis contribute to those limitations?
Figure 1 demonstrates a significant increase in collagen deposition within the vastus lateralis muscle of CKD patients. Histochemical analysis using picro-sirius red staining (A, B) revealed elevated total collagen content in CKD biopsies compared to controls, quantified in panel C. Stratification by diabetes status (D) further delineated collagen levels within the CKD cohort. Immunohistochemical staining highlighted increased collagen type 1 (E, F, G) and pro-collagen 1 expression (H) in CKD samples. Additionally, analysis of collagen hybridizing peptide (CHP) binding (I, J, L) indicated elevated levels of denatured collagen, suggesting active ECM remodeling, while collagen type 4 content (K) was also quantified. These data collectively support the observation of enhanced collagen accumulation and turnover in the vastus lateralis muscle of CKD patients.
Researchers compared stage 4 and 5 CKD patients with healthy volunteers, measuring physical function, body composition, serum creatine, urine urea nitrogen, and muscle biopsies. Immunohistochemical staining identified fibrotic features, including total collagen (Picro Sirius Red), Collagen I and IV, and damaged collagen (using CHPs).
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Total and damaged collagen content was increased in CKD patients, without a significant change in type IV collagen. The use of both Picro Sirius Red and CHPs provided insights into both total collagen and active remodeling. This indicated increased total collagen and accelerated remodeling, suggesting disease progression. Collagen content in the vastus lateralis muscle was negatively correlated with muscle strength and 2-minute walk distance, indicating an association between muscle fibrosis and impaired function. Additionally, the vastus lateralis muscle showed reduced expression of pro-inflammatory mRNA markers, suggesting localized dysregulation promoting fibrotic tissue development.
While fibrosis in CKD is often associated with the kidneys, muscle fibrosis may significantly impact patients. This study is among the first to examine ECM dysregulation in the context of CKD-related muscle weakness. By using both total collagen staining and CHP analysis for damaged collagen, researchers gained insight into both the extent of fibrosis and the rate of remodeling. This distinction is important for understanding disease progression. If muscle fibrosis plays such a significant role in CKD patient's quality of life, what targeted therapies could address these muscle related issues? Could understanding the dynamic remodeling of collagen open doors to earlier interventions, potentially slowing disease progression beyond kidney function alone? Understanding the broader context of fibrosis in CKD could expand treatment options and improve patient outcomes.