DNA methylation across the genome in aged human skeletal muscle tissue and muscle-derived cells: the role of HOX genes and physical activity.

Skeletal muscle tissue demonstrates global hypermethylation with age. However, methylome changes across the time-course of differentiation in aged human muscle derived cells, and larger coverage arrays in aged muscle tissue have not been undertaken. Using 850K DNA methylation arrays we compared the methylomes of young (27 ± 4.4 years) and aged (83 ± 4 years) human skeletal muscle and that of young/aged heterogenous muscle-derived human primary cells (HDMCs) over several time points of differentiation (0, 72 h, 7, 10 days). Aged muscle tissue was hypermethylated compared with young tissue, enriched for; pathways-in-cancer (including; focal adhesion, MAPK signaling, PI3K-Akt-mTOR signaling, p53 signaling, Jak-STAT signaling, TGF-beta and notch signaling), rap1-signaling, axon-guidance and hippo-signalling. Aged cells also demonstrated a hypermethylated profile in pathways; axon-guidance, adherens-junction and calcium-signaling, particularly at later timepoints of myotube formation, corresponding with reduced morphological differentiation and reductions in MyoD/Myogenin gene expression compared with young cells. While young cells showed little alterations in DNA methylation during differentiation, aged cells demonstrated extensive and significantly altered DNA methylation, particularly at 7 days of differentiation and most notably in focal adhesion and PI3K-AKT signalling pathways. While the methylomes were vastly different between muscle tissue and HDMCs, we identified a small number of CpG sites showing a hypermethylated state with age, in both muscle tissue and cells on genes KIF15, DYRK2, FHL2, MRPS33, ABCA17P. Most notably, differential methylation analysis of chromosomal regions identified three locations containing enrichment of 6-8 CpGs in the HOX family of genes altered with age. With HOXD10, HOXD9, HOXD8, HOXA3, HOXC9, HOXB1, HOXB3, HOXC-AS2 and HOXC10 all hypermethylated in aged tissue. In aged cells the same HOX genes (and additionally HOXC-AS3) displayed the most variable methylation at 7 days of differentiation versus young cells, with HOXD8, HOXC9, HOXB1 and HOXC-AS3 hypermethylated and HOXC10 and HOXC-AS2 hypomethylated. We also determined that there was an inverse relationship between DNA methylation and gene expression for HOXB1, HOXA3 and HOXC-AS3. Finally, increased physical activity in young adults was associated with oppositely regulating HOXB1 and HOXA3 methylation compared with age. Overall, we demonstrate that a considerable number of HOX genes are differentially epigenetically regulated in aged human skeletal muscle and HDMCs and increased physical activity may help prevent age-related epigenetic changes in these HOX genes.

Localised pigmented villonodular synovitis: an uncommon cause of knee pain mimicking a meniscal tear.

A previously well 30 year old man presented with a short history of intra-articular mechanical locking, swelling, and anteromedial joint line pain. There was localised tenderness, and McMurray's test was positive. Arthroscopy revealed a 3.6 x 2.6 x 1.5 cm firm pedicular localised pigmented villonodular synovitis originating from the insertion of the anterior horn of the medial meniscus. Owing to its size and consistency, mini-arthrotomy was required. This allowed a return to sporting activities. Localised pigmented villonodular synovitis can mimic symptoms of a meniscal tear.

Pyogenic vertebral osteomyelitis: treatment by anterior spinal debridement and fusion.

Forty-three patients with pathologically proven vertebral osteomyelitis were studied between 1957 and 1990. Thirty-nine underwent anterior debridement and fusion, and four underwent anterior debridement only. The indications for surgery were uncertain diagnosis, persistent pain, failed conservative treatment with uncontrolled sepsis, and neurological involvement. Thirty patients were followed-up for an average period of 5 years, with a minimum of 2 years and the longest for 15 years. All their symptoms improved after surgery; only one patient subsequently deteriorated due to multiple level recurrence. All patients with neurological deficit improved. Bony fusion occurred in 93% of cases (average time to fusion, 6.8 months), and 90% of the patients were able to return to their original work 4-20 months after surgery. We feel that anterior debridement and spinal fusion allow for reliable microbiological and histological diagnosis, and rapid relief of symptoms and return to work. Primary bone grafting is successful despite the presence of infection.