Overexpression of Latent TGFß Binding Protein 4 in Muscle Ameliorates Muscular Dystrophy through Myostatin and TGFß.

Latent TGFß binding proteins (LTBPs) regulate the extracellular availability of latent TGFß. LTBP4 was identified as a genetic modifier of muscular dystrophy in mice and humans. An in-frame insertion polymorphism in the murine Ltbp4 gene associates with partial protection against muscular dystrophy. In humans, nonsynonymous single nucleotide polymorphisms in LTBP4 associate with prolonged ambulation in Duchenne muscular dystrophy. To better understand LTBP4 and its role in modifying muscular dystrophy, we created transgenic mice overexpressing the protective murine allele of LTBP4 specifically in mature myofibers using the human skeletal actin promoter. Overexpression of LTBP4 protein was associated with increased muscle mass and proportionally increased strength compared to age-matched controls. In order to assess the effects of LTBP4 in muscular dystrophy, LTBP4 overexpressing mice were bred to mdx mice, a model of Duchenne muscular dystrophy. In this model, increased LTBP4 led to greater muscle mass with proportionally increased strength, and decreased fibrosis. The increase in muscle mass and reduction in fibrosis were similar to what occurs when myostatin, a related TGFß family member and negative regulator of muscle mass, was deleted in mdx mice. Supporting this, we found that myostatin forms a complex with LTBP4 and that overexpression of LTBP4 led to a decrease in myostatin levels. LTBP4 also interacted with TGFß and GDF11, a protein highly related to myostatin. These data identify LTBP4 as a multi-TGFß family ligand binding protein with the capacity to modify muscle disease through overexpression.

Excess SMAD signaling contributes to heart and muscle dysfunction in muscular dystrophy.

Disruption of the dystrophin complex causes muscle injury, dysfunction, cell death and fibrosis. Excess transforming growth factor (TGF) ß signaling has been described in human muscular dystrophy and animal models, where it is thought to relate to the progressive fibrosis that characterizes dystrophic muscle. We now found that canonical TGFß signaling acutely increases when dystrophic muscle is stimulated to contract. Muscle lacking the dystrophin-associated protein γ-sarcoglycan (Sgcg null) was subjected to a lengthening protocol to produce maximal muscle injury, which produced rapid accumulation of nuclear phosphorylated SMAD2/3. To test whether reducing SMAD signaling improves muscular dystrophy in mice, we introduced a heterozygous mutation of SMAD4 (S4) into Sgcg mice to reduce but not ablate SMAD4. Sgcg/S4 mice had improved body mass compared with Sgcg mice, which normally show a wasting phenotype similar to human muscular dystrophy patients. Sgcg/S4 mice had improved cardiac function as well as improved twitch and tetanic force in skeletal muscle. Functional enhancement in Sgcg/S4 muscle occurred without a reduction in fibrosis, suggesting that intracellular SMAD4 targets may be important. An assessment of genes differentially expressed in Sgcg muscle focused on those encoding calcium-handling proteins and responsive to TGFß since this pathway is a target for mediating improvement in muscular dystrophy. These data demonstrate that excessive TGFß signaling alters cardiac and muscle performance through the intracellular SMAD pathway.

Open Fractures in National Football League Athletes: Analyzing Performance and Return to Sport.

INTRODUCTION: Open fractures are potentially devastating injuries for the professional athlete. We sought to compare return to sports (RTS) and performance in National Football League (NFL) athletes sustaining open versus closed fractures. METHODS: NFL athletes with surgically treated open and closed fractures of the forearm, tibial shaft, and ankle from 2009-2018 were identified through publicly available reports and records. Data including demographics, RTS, career duration, and the approximate value performance metric before and after injury were collected. Statistical analyses were performed comparing open to closed injuries. Continuous variables were compared using Mann-Whitney U or two sample t- tests while categorical variables were compared using Fisher's exact test. RESULTS: Ninety-five athletes met inclusion criteria (10 open and 85 closed fractures). Overall, 90% (n = 9) returned to sport after an open injury and 83.5% (n = 71) returned after closed injury with a median time missed of 48.9 (range 35.1 - 117.4) weeks and 43.0 (range 2.4 - 108.0) weeks, respectively. Athletes undergoing forearm surgery were able to return sooner, at around 20.8 weeks, and ankle fractures conferred the lowest return rate at 80% (n = 48). There were no significant differences in career duration and post-injury performance between open or closed fracture cohorts. CONCLUSIONS: Although open fractures are relatively uncommon injuries seen in NFL athletes, our study suggests RTS for these players is high. Athletes undergoing surgical treatment for open fractures had similar RTS rates, performance metrics, and career durations compared to those with comparable closed fractures. This information can provide guidance for providers counseling elite athletes on postoperative expectations.

Growth Factor Expression During Healing in 3 Distinct Tendons.

Purpose: We investigated unique tendon growth-factor expression profiles over time in response to simultaneous, similar injuries. Characterizing these genetic differences lays the foundation for creating targeted, tendon-specific therapies and provides insight into why current growth-factor treatments have success in some applications but not others. Methods: The left fourth digital flexor, triceps, and supraspinatus tendons in 24 rats were cut to 50% of their transverse width at the midbelly under anesthesia. On postoperative days 1, 3, 5, 7, and 14, randomly selected rats were sacrificed, and the damaged tendons were excised and flash-frozen in liquid nitrogen. The expressional fibroblast growth factor 1, bone morphogenic protein 13, and transforming growth factor ß-1 were measured at each time point and compared to their respective, uninjured levels with real-time polymerase chain reaction. Results: The digital flexor tendon showed exponentially elevated expression of all 3 factors over the preinjury baseline values. Expression in the triceps and supraspinatus had more variation over time. The triceps tendon showed a considerable decrease of transforming growth factor ß-1 and bone morphogenic protein 13 expression. The supraspinatus tendon had statistically significant increases of both transforming growth factor ß-1 and bone morphogenic protein 13 expression relative to preoperative, uninjured levels, with a nonstatistically significant decrease of fibroblast growth factor 1. Conclusions: Our study suggests different tendons express their own unique growth-factor profiles after similar, simultaneous injuries. The digital flexor showed particularly high, sustained levels of growth-factor expression in comparison to the supraspinatus and triceps, suggesting that variable dosing may be necessary for growth-factor therapies aimed at supplementing innate responses in these different tendon types. Clinical relevance: These data show different tendons express unique trends of growth-factor expression over time in response to injury, suggesting each unique tendon may require specific dosing or knockdown therapies. These observations serve as a foundation for more tendon-specific questioning, experimentation, and therapeutic design.

Open Peroneal Tendon Stabilization With Fibular Groove Deepening.

Peroneal tendon subluxation often occurs because of sudden dorsiflexion of the ankle, leading to a traumatic rupture of the superior peroneal retinaculum. Currently, there are several surgical techniques to deepen the fibular groove, but there is no universally accepted gold standard. This technique article describes a fibular groove deepening with preservation of the fibrocartilage in conjunction with repair of the superior peroneal retinaculum. Addressing the main pathologies that may be leading to subluxation of the peroneal tendons, we offer an approach that avoids many of the common pitfalls from previously proposed techniques while preserving the natural fibrocartilage within the malleolar groove and repairing the retinaculum.

Single Knotless Suture Anchor Repair of Anterior Talofibular Ligament Following Distal Fibula Nonunion Excision.

Anterior talofibular ligament (ATFL) tear is the most common ankle ligament injury. This can lead to recurrent ankle instability, which is detrimental to ankle function and the patient's quality of life. Currently, several techniques have shown successful outcomes for ATFL repair. In this technical note, we describe an open ATFL repair using a single knotless suture anchor at the distal fibula location. This approach is rapid, equipment-efficient, and reproducible, while promising excellent results and high patient satisfaction by restoring ATFL anatomy.

Rehabilitation After Anterior Cruciate Ligament Injury: Review of Current Literature and Recommendations.

PURPOSE OF REVIEW: Anterior cruciate ligament reconstruction (ACLR) is a common surgical procedure with an estimated 120,000 cases performed in the USA each year. Physical therapy plays a critical role in the successful recovery of both surgically and non-surgically managed patients. Interestingly, ACL rehabilitation protocols vary greatly with little consensus among practitioners. Nonetheless, there has been agreement over the last decade to shift from conservative, standardized length protocols to more accelerated, individualized protocols that vary in length and modalities based on patient-specific findings and preferences. This review summarizes the most recent trends, opinions, and modalities in ACL rehabilitation research, with a specific focus on novel methods to treat the specific psychosocial needs of ACL deficient patients. RECENT FINDINGS: We found that new protocols emphasize early weight bearing, open kinetic chain (OKC) exercises, and other alternative modalities such as neuromuscular electrical stimulation and blood flow restriction. We also found a recent trend toward the use of clinical milestones to determine when a patient is ready for the next phase of a "step-up" rehabilitation program. One particularly nascent topic of research is the inclusion of methods to treat the psychosocial impacts of ACL injury, recovery, and the anxiety around return to sport. Rehabilitation strategy has become increasingly patient-dependent, and the new modalities being utilized are accelerating patient recovery. Return to sport is a particularly important factor for many ACLR patients, and recovery has an important psychological component that has only recently been addressed in the literature, with positive preliminary findings.

Mini-Open Achilles Repair With a Flat Braided Suture in a Low-Profile Configuration.

Achilles repair has evolved over the past 30 years, from large open procedures with high complication rates to shorter, less-invasive procedures with better outcomes. Percutaneous repair has comparable failure rates with open repairs, fewer complications, and faster recovery. However, percutaneous Achilles repairs risk sural nerve injury. A mini-open repair fuses the gap between percutaneous and open procedures, and this approach has the potential to mitigate nerve injury while maintaining the increased efficiency in procedure time and patient recovery. The purpose of this Technical Note and accompanying video is to outline the repair of the Achilles tendon using a mini open repair using a low-profile flat braided suture.

Stemless Total Shoulder Arthroplasty With Orthobiologic Augmentation.

Total shoulder arthroplasty (TSA) has evolved over the years and is used for a variety of indications, with arthritis being the most common. Stemless TSA is a unique bone-preserving design that can eliminate rotational malalignment. Additionally, recent literature has found utility in the use of biological mesh and a platelet-rich plasma injection to improve healing. The purpose of this article is to outline the process of TSA using a stemless system and how to incorporate the use of amnion matrix and platelet-rich plasma into the surgical technique.

Cardiac function in muscular dystrophy associates with abdominal muscle pathology.

BACKGROUND: The muscular dystrophies target muscle groups differentially. In mouse models of muscular dystrophy, notably the mdx model of Duchenne Muscular Dystrophy, the diaphragm muscle shows marked fibrosis and at an earlier age than other muscle groups, more reflective of the histopathology seen in human muscular dystrophy. METHODS: Using a mouse model of limb girdle muscular dystrophy, the Sgcg mouse, we compared muscle pathology across different muscle groups and heart. A cohort of nearly 200 Sgcg mice were studied using multiple measures of pathology including echocardiography, Evans blue dye uptake and hydroxyproline content in multiple muscle groups. Spearman rank correlations were determined among echocardiographic and pathological parameters. FINDINGS: The abdominal muscles were found to have more fibrosis than other muscle groups, including the diaphragm muscle. The abdominal muscles also had more Evans blue dye uptake than other muscle groups. The amount of diaphragm fibrosis was found to correlate positively with fibrosis in the left ventricle, and abdominal muscle fibrosis correlated with impaired left ventricular function. Fibrosis in the abdominal muscles negatively correlated with fibrosis in the diaphragm and right ventricles. Together these data reflect the recruitment of abdominal muscles as respiratory muscles in muscular dystrophy, a finding consistent with data from human patients.