A Novel Muscle Atrophy Mechanism: Myocyte Degeneration Due to Intracellular Iron Deprivation.

Muscle atrophy is defined as the progressive degeneration or shrinkage of myocytes and is triggered by factors such as aging, cancer, injury, inflammation, and immobilization. Considering the total amount of body iron stores and its crucial role in skeletal muscle, myocytes may have their own iron regulation mechanism. Although the detrimental effects of iron overload or iron deficiency on muscle function have been studied, the molecular mechanism of iron-dependent muscle atrophy has not been elucidated. Using human muscle tissues and in the mouse rotator cuff tear model, we confirmed an association between injury-induced iron depletion in myocytes and muscle atrophy. In differentiated C2C12 myotubes, the effects of iron deficiency on myocytes and the molecular mechanism of muscle atrophy by iron deficiency were evaluated. Our study revealed that the lower iron concentration in injured muscle was associated with the upregulation of ferroportin, an iron exporter that transports iron out of cells. Ferroportin expression was increased by hypoxia-inducible factor 1α (HIF1α), which is activated by muscle injury, and its expression is controlled by HIF1 inhibitor treatment. Iron deprivation caused myocyte loss and a marked depletion of mitochondrial membrane potential leading to muscle atrophy, together with increased levels of myostatin, the upstream regulator of atrogin1 and muscle RING-finger protein-1 (MuRF1). Myostatin expression under iron deficiency was mediated by an orphan nuclear receptor, dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome (DAX1).

Remnant preservation with tensioning can improve the clinical outcome after anterior cruciate ligament reconstruction.

BACKGROUND: Many studies exist about remnant preservation in anterior cruciate ligament (ACL) reconstruction. However, concern remains for development of a cyclops lesion during remnant preservation. To prevent this, a tensioning method has been suggested. Current study evaluated the clinical and radiologic results of remnant preservation in ACL reconstruction with tensioning compared to classical ACL reconstruction. METHODS: From January 2016 to June 2017, ACL reconstruction patients who underwent magnetic resonance imaging (MRI) 2 years postoperatively were enrolled. For comparison, all participants were divided in two groups: remnant preservation with tensioning (group R) and controls (group C). Clinically, Hospital for Special Surgery (HSS), International Knee Documentation Committee (IKDC), Lysholm scores, and incidence of symptomatic cyclops lesions were evaluated. Radiologically, signal-to-noise quotient (SNQ) and size of the synovium on MRI as well as anterior instability in Telos stress radiographs were evaluated. RESULTS: A total of 64 patients were enrolled (42 in group R and 22 in group C). The IKDC score in group R (70) was better than that in group C (62; p < 0.05). One patient in group R had a cyclops lesion with clinical symptoms and arthroscopic excision was recommended. Radiologically, the SNQ, synovium area, and anterior instability on Telos radiography showed no difference between the two groups. CONCLUSION: Remnant preservation with tensioning is a good option for ACL reconstruction without the development of a cyclops lesion.

Differential regulation of the water channel protein aquaporins in chondrocytes of human knee articular cartilage by aging.

Knee cartilage is in an aqueous environment filled with synovial fluid consisting of water, various nutrients, and ions to maintain chondrocyte homeostasis. Aquaporins (AQPs) are water channel proteins that play an important role in water exchange in cells, and AQP1, -3, and -4 are known to be expressed predominantly in cartilage. We evaluated the changes in AQP expression in chondrocytes from human knee articular cartilage in patients of different ages and identified the key factor(s) that mediate age-induced alteration in AQP expression. The mRNA and protein expression of AQP1, -3 and -4 were significantly decreased in fibrocartilage compared to hyaline cartilage and in articular cartilage from older osteoarthritis patients compared to that from young patients. Gene and protein expression of AQP1, -3 and -4 were altered during the chondrogenic differentiation of C3H10T1/2 cells. The causative factors for age-associated decrease in AQP included H2O2, TNFα, and HMGB1 for AQP1, -3, and -4, respectively. In particular, the protective effect of AQP4 reduction following HMGB1 neutralization was noteworthy. The identification of other potent molecules that regulate AQP expression represents a promising therapeutic approach to suppress cartilage degeneration during aging.

Human umbilical cord-blood-derived mesenchymal stem cell can improve the clinical outcome and Joint space width after high tibial osteotomy.

BACKGROUND: There is limited study about the human umbilical cord-blood derived mesenchymal stem cell (hUCB-MSC) cartilage regeneration procedures combined with high tibial osteotomy (HTO). We compared the clinical and radiological results of hUCB-MSC cartilage regeneration procedures combined with HTO to those of microfracture with HTO. METHODS: From August 2017 to December 2018, HTO patients with International Cartilage Regeneration and Joint Preservation Society (ICRS) grade IV cartilage defects over 200 mm2 on medial femoral condyle (MFC) were enrolled. For comparison, all participants were divided into two groups: those who had undergone an hUCB-MSC induced cartilage regeneration procedure (group MSC) and those with microfractures only (group C, controls). Clinically, Hospital for Special Surgery (HSS), International Knee Documentation Committee (IKDC), and Lysholm scores were evaluated post-operatively at 18 months. Radiologically, mechanical axis (MA) and joint space width (JSW) were evaluated. RESULTS: A total of 100 knees were enrolled (43 in group MSC, 57 in group C). The IKDC score in group MSC (69) was better than that in group C (62; P < 0.05). The JSW increment in the MSC group (0.6 mm) was more than that in group C (0.1 mm; P < 0.05). No patient developed nonunion, correction loss, or arthroplasty conversion. CONCLUSION: hUCB-MSCs can improve clinical outcome and JSW better than microfracture only in HTO patients.

Simple Medial Meniscus Posterior Horn Root Repair Using an All-Inside Meniscal Repair Device Combined with High Tibial Osteotomy to Maintain Joint-Space Width in a Patient with a Repairable Tear.

PURPOSE: To compare the radiological and clinical outcomes using simple medial meniscus posterior horn (MMPH) root repair using an all-inside meniscal repair device combined with high tibial osteotomy (HTO) and HTO alone. METHODS: Between November 2013 and December 2016, patients treated for MMPH root tear along with HTO were enrolled. Based on the tear gap, the participants were divided into repairable (< 2 mm) and unrepairable (> 2 mm) categories. The participants in each group were divided into those amenable to simple MMPH root repair using an all-inside meniscal repair device and those that required no procedure for meniscus. Radiological parameters including mechanical femorotibial alignment (MA), posterior tibial slope (PTS) and medial joint-space width (JSW) were evaluated preoperatively and postoperatively at 2 years. For clinical evaluation, the WOMAC score was determined at the 2-year visit postoperatively. RESULTS: A total of 81 knees including 48 repairable (group R) and 33 unrepairable (group I) knees were enrolled. A total of 43 knees underwent simple MMPH root repair using an all-inside meniscal repair device (subgroup r), whereas the other 38 knees did not (subgroup n). The MA, PTS, and their postoperative changes as well as the WOMAC scores showed no differences. However, the JSW in group Rr increased from 3.1 to 3.6 mm, but decreased from 3.7 to 3.4 in group Rn, which was a statistically significant difference. CONCLUSION: Simple MMPH root repair using an all-inside meniscal repair device combined with HTO was more effective for the maintenance of JSW compared with HTO without a meniscal procedure in patients with repairable MMPH root tear and varus alignment. However, other options are needed for unrepairable MMPH root tear.

Atrogin1-induced loss of aquaporin 4 in myocytes leads to skeletal muscle atrophy.

The water channel aquaporin 4 (AQP4) regulates the flux of water across the cell membrane, maintaining cellular homeostasis. Since AQP4 is enriched in the sarcolemma of skeletal muscle, a functional defect in AQP4 may cause skeletal muscle dysfunction. To investigate a novel mechanism underlying skeletal muscle atrophy, we examined AQP4 expression and its regulation in muscle using the rotator cuff tear (RCT) model. Human and mouse AQP4 expression was significantly decreased in atrophied muscle resulting from RCT. The size and the number of myotubes were reduced following AQP4 knockdown. Atrogin 1-mediated ubiquitination of AQP4 was verified with an ubiquitination assay after immunoprecipitation of AQP4 with an anti-AQP4 antibody. In this study, we identified high mobility group box 1 (HMGB1) as a potent upstream regulator of atrogin 1 expression. Atrogin 1 expression was increased by recombinant mouse HMGB1 protein, and the HMGB1-induced atrogin 1 expression was mediated via NF-κB signaling. Our study suggests that loss of AQP4 appears to be involved in myocyte shrinkage after RCT, and its degradation is mediated by atrogin 1-dependent ubiquitination. HMGB1, in its function as a signaling molecule upstream of the ubiquitin ligase atrogin 1, was found to be a novel regulator of muscle atrophy.

Tunnel widening prevention with the allo-Achilles tendon graft in anterior cruciate ligament reconstruction: Surgical tips and short term followup.

BACKGROUND: Tunnel widening (TW) after anterior cruciate ligament (ACL) reconstruction can be a serious complication, and there is controversy over how to prevent it. This study aimed to suggest surgical approaches to prevent TW using an allo-Achilles tendon graft, and then to evaluate TW after these surgical tips were applied. MATERIALS AND METHODS: Sixty two patients underwent ACL reconstruction with an allo-Achilles tendon graft. Four surgical approaches were used: Making a tibial tunnel by bone impaction, intraarticular reamer application, bone portion application for the femoral tunnel, and an additional bone plug application for the tibial tunnel. After more than 1-year, followup radiographs including anteroposterior and lateral views were taken in 29 patients encompassing thirty knees. The diameter of the tunnels at postoperation day 1 (POD1) and at followup was measured and compared. RESULTS: In 18 knees (60%), there were no visible femoral tunnel margins on the radiographs at POD1 or followup. In the other 12 cases, which had visible femoral tunnel margins on followup radiographs, the mean femoral tunnel diameter was 8.6 mm. In the tibial tunnel, the mean diameters did not increase on all three levels (proximal, middle, and distal), and there was no statistically significant difference between the diameters at POD1 and followup. CONCLUSION: The suggested tips for surgery involving an allo-Achilles tendon graft can effectively prevent TW after ACL reconstruction according to this case series. These surgical tips can prevent TW.

Gel-type autologous chondrocyte (Chondron) implantation for treatment of articular cartilage defects of the knee.

BACKGROUND: Gel-type autologous chondrocyte (Chondron) implantations have been used for several years without using periosteum or membrane. This study involves evaluations of the clinical results of Chondron at many clinical centers at various time points during the postoperative patient follow-up. METHODS: Data from 98 patients with articular cartilage injury of the knee joint and who underwent Chondron implantation at ten Korean hospitals between January 2005 and November 2008, were included and were divided into two groups based on the patient follow-up period, i.e. 13~24-month follow-up and greater than 25-month follow-up. The telephone Knee Society Score obtained during telephone interviews with patients, was used as the evaluation tool. RESULTS: On the tKSS-A (telephone Knee Society Score-A), the score improved from 43.52 +/- 20.20 to 89.71 +/- 13.69 (P < 0.05), and on the tKSS-B (telephone Knee Society Score-B), the score improved from 50.66 +/- 20.05 to 89.38 +/- 15.76 (P < 0.05). The total improvement was from 94.18 +/- 31.43 to 179.10 +/- 24.69 (P < 0.05). CONCLUSION: Gel-type autologous chondrocyte implantation for chondral knee defects appears to be a safe and effective method for both decreasing pain and improving knee function.