Pharmacological inhibition of myostatin protects against skeletal muscle atrophy and weakness after anterior cruciate ligament tear

Abstract

Anterior cruciate ligament (ACL) tears are among the most frequent knee injuries in sports medicine, with tear rates in the US up to 250,000 per year. Many patients who suffer from ACL tears have persistent atrophy and weakness even after considerable rehabilitation. Myostatin is a cytokine that directly induces muscle atrophy, and previous studies rodent models and patients have demonstrated an upregulation of myostatin after ACL tear. Using a preclinical rat model, our objective was to determine if the use of a bioneutralizing antibody against myostatin could prevent muscle atrophy and weakness after ACL tear. Rats underwent a surgically induced ACL tear and were treated with either a bioneutralizing antibody against myostatin (10B3, GlaxoSmithKline) or a sham antibody (E1-82.15, GlaxoSmithKline). Muscles were harvested at either 7 or 21 days after induction of a tear to measure changes in contractile function, fiber size and genes involved in muscle atrophy and hypertrophy. These time points were selected to evaluate early and later changes in muscle structure and function. Compared to the sham antibody group, seven days after ACL tear, myostatin inhibition reduced the expression of proteolytic genes and induced the expression of hypertrophy genes. These early changes in gene expression lead to a 22% increase in muscle fiber cross-sectional area and a 10% improvement in maximum isometric force production that were observed 21 days after ACL tear. Overall, myostatin inhibition lead to several favorable, although modest, changes in molecular biomarkers of muscle regeneration and reduced muscle atrophy and weakness following ACL tear.

Anterior cruciate ligament tear induces a sustained loss of muscle fiber force production

“…This is further supported by animal studies that reported reduced in vitro whole muscle force production after ACL tear, with increased expression of atrophy‐associated genes such as the E3 ubiquitin ligases atrogin‐1, MuRF‐1, and MUSA‐1 that can target proteins for enzymatic breakdown . In the current study, the lack of appreciable changes in fiber CSA along with substantial changes in F o , suggest that there is a marked reduction in the density of myofibrils, which are the force generating organelles in muscle fibers.…”

“…16,17 This is further supported by animal studies that reported reduced in vitro whole muscle force production after ACL tear, with increased expression of atrophy-associated genes such as the E3 ubiquitin ligases atrogin-1, MuRF-1, and MUSA-1 that can target proteins for enzymatic breakdown. 18,19 In the current study, the lack of appreciable changes in fiber CSA along with substantial changes in F o , suggest that there is a marked reduction in the density of myofibrils, which are the force generating organelles in muscle fibers. Although speculative, the results of the current manuscript and previous studies suggest that it is possible that after ACL tear and surgical reconstruction there is an initial activation of proteolytic processes within fibers that lead to a reduction in force production through loss of myofibrils.…”

The effect of exercise on the protein profile of rat knee joint intra- and extra-articular ligaments

“…Injuries to the ACL together with the extra-articular medial collateral ligament (MCL), account for over 95% of all multi-ligament injuries in the knee joint [4,5], resulting in significant joint instability and causing major physical, social [6] and financial implications [7]. ACL injuries can also lead to significant functional impairment in athletes as a result of joint instability and muscle atrophy, and are associated with the development of osteoarthritis [5,8] leading to a major clinical challenge in orthopaedic medicine [9].…”

The Effects of Anterior Cruciate Ligament Reconstruction on Individual Quadriceps Muscle Thickness and Circulating Biomarkers

“…The purpose of this study was to determine the effect of ACLR on individual quadriceps muscle thickness and circulating biomarkers. Previous studies have reported that many patients suffered quadriceps atrophy for several months to years after ACLR [2,27]. However, it is unclear how individual components of the quadriceps decreased in size a week after ACLR.…”

“…Myostatin is the representative atrophy-inducing cytokine. Several studies have reported that mutations in the myostatin gene induce tremendous hypertrophy [19,27]. However, in physiologically normal conditions, myostatin induces muscle atrophy via the Fox O pathway and interacts with the activin receptor complex to prevent unopposed activin-induced muscle hypertrophy via a signaling cascade [19,29].…”