T1ρ imaging as a non‐invasive assessment of collagen remodelling and organization in human skeletal muscle after ligamentous injury

Abstract

Dysregulation and fibrosis of the extracellular matrix (ECM) in skeletal muscle is a consequence of injury. Current ECM assessment necessitates muscle biopsies to evaluate alterations to the muscle ECM, which is often not practical in humans. The goal of this study was to evaluate the potential of a magnetic resonance imaging sequence that quantifies T1ρ relaxation time to predict ECM collagen composition and organization. T1ρ imaging was performed and muscle biopsies obtained from the involved and non‐involved vastus lateralis muscle on 27 subjects who had an anterior cruciate ligament (ACL) tear. T1ρ times were quantified via monoexponential decay curve fitted to a series of T1ρ‐weighted images. Several ECM indices, including collagen content and organization, were obtained using immunohistochemistry and histochemistry in addition to hydroxyproline. Model selection with multiple linear regression was used to evaluate the relationships between T1ρ times and ECM composition. Additionally, the ACL‐deficient and healthy limb were compared to determine sensitivity of T1ρ to detect early adaptations in the muscle ECM following injury. We show that T1ρ relaxation time was strongly associated with collagen unfolding (t = 4.093, P = 0.0007) in the ACL‐deficient limb, and collagen 1 abundance in the healthy limb (t = 2.75, P = 0.014). In addition, we show that T1ρ relaxation time is significantly longer in the injured limb, coinciding with significant differences in several indices of collagen content and remodelling in the ACL‐deficient limb. These results support the use of T1ρ to evaluate ECM composition in skeletal muscle in a non‐invasive manner. imageKey points Dysregulation and fibrotic transformation of the skeletal muscle extracellular matrix (ECM) is a common pathology associated with injury and ageing. Studies of the muscle ECM in humans have necessitated the use of biopsies, which are impractical in many settings. Non‐invasive MRI T1ρ relaxation time was validated to predict ECM collagen composition and organization with aligned T1ρ imaging and biopsies of the vastus lateralis in the healthy limb and anterior cruciate ligament (ACL)‐deficient limb of 27 subjects. T1ρ relaxation time was strongly associated with collagen abundance and unfolding in the ACL‐deficient limb, and T1ρ relaxation time was strongly associated with total collagen abundance in the healthy limb. T1ρ relaxation time was significantly longer in the ACL‐deficient limb, coinciding with significant increases in several indices of muscle collagen content and remodelling supporting the use of T1ρ to non‐invasively evaluate ECM composition and pathology in skeletal muscle.

Depressed Protein Synthesis and Anabolic Signaling Potentiate ACL Tear–Resultant Quadriceps Atrophy

“…Mouse quadriceps myonuclei showed significant upregulation of pathways enriched for extracellular matrix organization and degradation in the ACLT limb. Recent work underscores collagen and extracellular matrix remodeling within the quadriceps after ACL injury, 15,46,47,52 and our current data show that murine myonuclei may contribute to extracellular matrix turnover in the ACL-injured quadriceps. Muscle fibers have an underappreciated role in extracellular matrix remodeling, 6,43 but our results suggest that murine quadriceps myonuclei are active participants in the remodeling of their extracellular niche after ACL injury.…”

GDF8 inhibition enhances musculoskeletal recovery and mitigates posttraumatic osteoarthritis following joint injury

“…Our previous work indicates sustained quadriceps fibrosis after ACL injury ( 25 , 32 , 40 ) that persists in patients with knee OA ( 26 , 27 ). We also report that GDF8 induces human muscle fibroblast proliferation and predicts FAP abundance following ACL injury ( 9 ).…”

“…S10, A to C). Sirius Red–stained slides were also imaged under polarized light to quantify dense (red), intermediate (yellow), and loose (green) collagen ( 39 , 40 ). Quadriceps muscle in placebo-treated animals increased loose and intermediate collagen 1 week after ACLT with an increase in dense collagen 2 weeks after ACLT (fig.…”

“…We observed a significant down-regulation of pathways concerning ECM organization, collagen biosynthesis, and cross-linking with anti-GDF8 treatment in the ACLT limb. Dosing acutely after injury may reflect the intervention window in the ACLT injury model, given the rapid onset of collagen remodeling after the initial ACL tear ( 9 , 40 ).…”

Vitamin D status associates with skeletal muscle loss after anterior cruciate ligament reconstruction

“…The present manuscript uses CSA, BMD, strength/power measures, and an RNA-seq data set that were collected during the parent study. To maximize the benefit of this observational study, collected samples have been used to answer different research questions ( 55 , 56 ).…”