Bioenergetic status modulates motor neuron vulnerability and pathogenesis in a zebrafish model of spinal muscular atrophy

Degeneration and loss of lower motor neurons is the major pathological hallmark of spinal muscular atrophy (SMA), resulting from low levels of ubiquitously-expressed survival motor neuron (SMN) protein. One remarkable, yet unresolved, feature of SMA is that not all motor neurons are equally affected, with some populations displaying a robust resistance to the disease. Here, we demonstrate that selective vulnerability of distinct motor neuron pools arises from fundamental modifications to their basal molecular profiles. Comparative gene expression profiling of motor neurons innervating the extensor digitorum longus (disease-resistant), gastrocnemius (intermediate vulnerability), and tibialis anterior (vulnerable) muscles in mice revealed that disease susceptibility correlates strongly with a modified bioenergetic profile. Targeting of identified bioenergetic pathways by enhancing mitochondrial biogenesis rescued motor axon defects in SMA zebrafish. Moreover, targeting of a single bioenergetic protein, phosphoglycerate kinase 1 (Pgk1), was found to modulate motor neuron vulnerability in vivo. Knockdown of pgk1 alone was sufficient to partially mimic the SMA phenotype in wild-type zebrafish. Conversely, Pgk1 overexpression, or treatment with terazosin (an FDA-approved small molecule that binds and activates Pgk1), rescued motor axon phenotypes in SMA zebrafish. We conclude that global bioenergetics pathways can be therapeutically manipulated to ameliorate SMA motor neuron phenotypes in vivo

The anterolateral complex of the knee: results from the International ALC Consensus Group Meeting

The structure and function of the anterolateral complex (ALC) of the knee has created much controversy since the 're-discovery' of the anterolateral ligament (ALL) and its proposed role in aiding control of anterolateral rotatory laxity in the anterior cruciate ligament (ACL) injured knee. A group of surgeons and researchers prominent in the field gathered to produce consensus as to the anatomy and biomechanical properties of the ALC. The evidence for and against utilisation of ALC reconstruction was also discussed, generating a number of consensus statements by following a modified Delphi process. Key points include that the ALC consists of the superficial and deep aspects of the iliotibial tract with its Kaplan fibre attachments on the distal femur, along with the ALL, a capsular structure within the anterolateral capsule. A number of structures attach to the area of the Segond fracture including the capsule-osseous layer of the iliotibial band, the ALL and the anterior arm of the short head of biceps, and hence it is not clear which is responsible for this lesion. The ALC functions to provide anterolateral rotatory stability as a secondary stabiliser to the ACL. Whilst biomechanical studies have shown that these structures play an important role in controlling stability at the time of ACL reconstruction, the optimal surgical procedure has not yet been defined clinically. Concern remains that these procedures may cause constraint of motion, yet no clinical studies have demonstrated an increased risk of osteoarthritis development. Furthermore, clinical evidence is currently lacking to support clear indications for lateral extra-articular procedures as an augmentation to ACL reconstruction. The resulting statements and scientific rationale aim to inform readers on the most current thinking and identify areas of needed basic science and clinical research to help improve patient outcomes following ACL injury and subsequent reconstruction. Level of evidence V

Diagnosis and treatment of rotatory knee instability

BACKGROUND Rotatory knee instability is an abnormal, complex three-dimensional motion that can involve pathology of the anteromedial, anterolateral, posteromedial, and posterolateral ligaments, bony alignment, and menisci. To understand the abnormal joint kinematics in rotatory knee instability, a review of the anatomical structures and their graded role in maintaining rotational stability, the importance of concomitant pathologies, as well as the different components of the knee rotation motion will be presented. MAIN BODY The most common instability pattern, anterolateral rotatory knee instability in an anterior cruciate ligament (ACL)-deficient patient, will be discussed in detail. Although intra-articular ACL reconstruction is the gold standard treatment for ACL injury in physically active patients, in some cases current techniques may fail to restore native knee rotatory stability. The wide range of diagnostic options for rotatory knee instability including manual testing, different imaging modalities, static and dynamic measurement, and navigation is outlined. As numerous techniques of extra-articular tenodesis procedures have been described, performed in conjunction with ACL reconstruction, to restore anterolateral knee rotatory stability, a few of these techniques will be described in detail, and discuss the literature concerning their outcome. CONCLUSION In summary, the essence of reducing anterolateral rotatory knee instability begins and ends with a well-done, anatomic ACL reconstruction, which may be performed with consideration of extra-articular tenodesis in a select group of patients