Changes in circulating biomarkers of muscle atrophy, inflammation, and cartilage turnover in patients undergoing anterior cruciate ligament reconstruction and rehabilitation

Abstract

Background: After anterior cruciate ligament (ACL) reconstruction, there is significant atrophy of the quadriceps muscles that can limit full recovery and place athletes at risk for recurrent injuries with return to play. The cause of this muscle atrophy is not fully understood.

Hypothesis: Circulating levels of proatrophy, proinflammatory, and cartilage turnover cytokines and biomarkers would increase after ACL reconstruction.

Study design: Descriptive laboratory study.

Methods: Patients (N = 18; mean age, 28 ± 2.4 years) underwent surgical reconstruction of the ACL after a noncontact athletic injury. Circulating levels of biomarkers were measured along with Short Form-12, International Knee Documentation Committee, and objective knee strength measures preoperatively and at 6 postoperative visits. Differences were tested using repeated-measures 1-way analysis of variance.

Results: Myostatin, TGF-β, and C-reactive protein levels were significantly increased in the early postoperative period and returned to baseline. Cartilage oligomeric matrix protein levels decreased immediately after surgery and then returned to baseline. CCL2, CCL3, CCL4, CCL5, EGF, FGF-2, IGF-1, IL-10, IL-1α, IL-1β, IL-1ra, IL-6, myoglobin, and TNF-α were not different over the course of the study.

Conclusion: An increase in potent atrophy-inducing cytokines and corresponding changes in knee strength and functional scores were observed after ACL reconstruction.

Clinical relevance: Although further studies are necessary, the therapeutic inhibition of myostatin may help prevent the muscle atrophy that occurs after ACL reconstruction and provide an accelerated return of patients to sport.

Keywords: ACL reconstruction; C-reactive protein; cartilage oligomeric matrix protein; muscle atrophy; myostatin; transforming growth factor-β.

Figure 1

Overview of the study design.

Figure 2

Changes in outcomes scores over the course of the study. (A) SF-12 physical component summary (PCS) score, (B) SF-12 mental component summary (MCS) score and (C) IKDC score. Vertical dashed line indicates the time of surgery. Values are mean±SE. N=18 subjects at each time point. *, significantly different from the pre-operative time point (P<0.05).

Figure 3

Changes in isometric and isokinetic strength over the course of the study. (A) Maximum isometric knee flexion force at 45° of knee flexion, (B) Maximum isometric knee extension force at 45° of knee flexion, (C) Maximum isometric knee flexion force at 90° of knee flexion, (D) Maximum isometric knee extension force at 90° of knee flexion, (E) Maximum isokinetic knee flexion force, and (F) Maximum isometric knee extension force. All force values of the involved limb were normalized to the uninvolved limb at each time point. Vertical dashed line indicates the time of surgery. Values are mean±SE. N=18 subjects at each time point. *, significantly different from the pre-operative time point (P<0.05).

Figure 4

Changes in plasma levels of biomarkers over the course of the study. (A) CCL2, (B) CCL3, (C) CCL4, (D) CCL5, (E) COMP, (F) CRP, (G) EGF, (H) FGF-2, (I) IGF-1, (J) IL-1α, (K) IL-1β, (L) IL-1ra, (M) IL-6, (N) IL-10, (O) myoglobin, (P) myostatin, (Q) TGF-β, and (R) TNF- α. Vertical dashed line indicates the time of surgery. Values are mean±SE. N=18 subjects at each time point. *, significantly different from the pre-operative time point (P<0.05).