Purpose of Review Osteoarthritis (OA) is a subset of joint disorders resulting in degeneration of synovial joints. This leads to pain, disability and loss of independence. Knee and hip OA are extremely prevalent, and their occurrence increases with ageing. Similarly, loss of muscle mass and function, sarcopenia, occurs during ageing. Recent Findings Little is known about the impact of muscle wasting on OA progression; nevertheless, it has been suggested that muscle wasting directly affects the stability of the joints and loss of mobility leads to gradual degeneration of articular cartilage. The molecular mechanisms underlying muscle wasting in OA are not well understood; however, these are probably related to changes in gene expression, as well as epigenetic modifications. Summary It is becoming clear that skeletal muscle wasting plays an important role in OA development and/or progression. Here, we discuss mechanisms, current interventions, such as exercise, and potentially novel approaches, such as modulation of microRNAs, aiming at ameliorating OA symptoms through maintaining muscle mass and function.

Osteoarthritis, the most common joint disorder, is characterised by deterioration of the articular cartilage. Many studies have identified potential therapeutic targets, yet no effective treatment has been determined. The aim of this study was to identify and rank osteoarthritis-associated genes and micro-RNAs to prioritise those most integral to the disease. A systematic meta-analysis of differentially expressed mRNA and micro-RNAs in human osteoarthritic cartilage was conducted. Ingenuity pathway analysis identified cellular senescence as an enriched pathway, confirmed by a significant overlap (p < 0.01) with cellular senescence drivers (CellAge Database). A co-expression network was built using genes from the meta-analysis as seed nodes and combined with micro-RNA targets and SNP datasets to construct a multi-source information network. This accumulated and connected 1689 genes which were ranked based on node and edge aggregated scores. These bioinformatic analyses were confirmed at the protein level by mass spectrometry of the different zones of human osteoarthritic cartilage (superficial, middle, and deep) compared to normal controls. This analysis, and subsequent experimental confirmation, revealed five novel osteoarthritis-associated proteins (PPIB, ASS1, LHDB, TPI1, and ARPC4-TTLL3). Focusing future studies on these novel targets may lead to new therapies for osteoarthritis.

The ryanodine receptor type 1 (RyR1) is a Ca2+ release channel that regulates skeletal muscle contraction by controlling Ca2+ release from the sarcoplasmic reticulum (SR). Posttranslational modifications (PTMs) of RyR1, such as phosphorylation, S-nitrosylation, and carbonylation are known to increase RyR1 open probability (Po), contributing to SR Ca2+ leak and skeletal muscle dysfunction. PTMs on RyR1 have been linked to muscle dysfunction in diseases like breast cancer, rheumatoid arthritis, Duchenne muscle dystrophy, and aging. While reactive oxygen species (ROS) and oxidative stress induce PTMs, the impact of stable oxidative modifications like 3-nitrotyrosine (3-NT) and malondialdehyde adducts (MDA) on RyR1 gating remains unclear. Mass spectrometry and single-channel recordings were used to study how 3-NT and MDA modify RyR1 and affect Po. Both modifications increased Po in a dose-dependent manner, with mass spectrometry identifying 30 modified residues out of 5035 amino acids per RyR1 monomer. Key modifications were found in domains critical for protein interaction and channel activation, including Y808/3NT in SPRY1, Y1081/3NT and H1254/MDA in SPRY2&3, and Q2107/MDA and Y2128/3NT in JSol, near the binding site of FKBP12. Though these modifications did not directly overlap with FKBP12 binding residues, they promoted FKBP12 dissociation from RyR1. These findings provide detailed insights into how stable oxidative PTMs on RyR1 residues alter channel gating, advancing our understanding of RyR1-mediated Ca2+ release in conditions associated with oxidative stress and muscle weakness.

The analysis of human genomes has revealed an unexpectedly large variability among individuals of a population. This variation occurs via numerous different mechanisms and on many different scales, ranging from single nucleotide changes to the loss or gain of lengths of DNA encompassing entire genes. Research has often found associations between DNA sequence variations, such as single-nucleotide polymorphisms, and common human diseases (Shastry, 2002). However, research into the relationship between copy number variations (CNVs) and disease is relatively novel, with progress only being made in recent years. Here, I review literature on the relationship between CNV and obesity including the advances and challenges involved in such research.

Articular soft tissue mineralization and ossification are clear pathological signs of osteoarthritis joints. However their molecular and cellular aetiologies remain largely unknown. TGF-ß family members are known contributors to both pathological ossification and osteoarthritis development. In this study, we used a Fibrillin-1 mutant mouse, the Tight Skin mouse (TSK), to define the detrimental effects of abnormal Fbn1 in TSK mice and known high TGF-ß activity in joint pathology such as articular soft tissue mineralization and ossification. Knee joints of male and Female TSK and Wild-type (WT) littermates were analysed my micro-CT imaging and histology for articular soft tissue pathologies, as well as OA severity. Both aged (10, 26, 35 and 52wks) and following in vivo non-invasive repetitive joint overloading were used. We find that male TSK mice develop spontaneous soft tissue ossification from 26wks of age, followed by increased osteoarthritis at 1 year-old. In addition, knee joint overloading induced ligament and meniscal mineralisation and ossification in both WT and TSK male mice, but were significantly more severe in TSK knees, including ossification of the patella ligament and synovial lining. In contrast, female TSK knees did not develop more severe soft tissue mineralisation compared to littermate WT mice in neither aged nor overloaded knees. We conclude that Fbn1 mutation, and possibly overactive TGF-ß activity in TSK mice, induce articular soft tissue ossification and osteoarthritis in a sex-specific manner. Further studies are needed to confirm the specific signalling involved and the relative protection from female mice from such pathologies.

Objective: Rheumatoid arthritis (RA) is a common chronic systemic inflammatory disease that causes musculoskeletal impairments and fatigue. Physical activity is recommended for individuals with RA, and health-enhancing physical activity (HEPA) has been shown to improve health perception and physical fitness in this group. However, the molecular adaptations of skeletal muscle in response to an exercise intervention are still unexplored in individuals with RA. This study aimed to assess the skeletal muscle response to a 2-year HEPA intervention in individuals with RA. Methods: Thirteen individuals with RA (65 ± 2 years old, 13 ± 2 years disease duration) participated. The 2-year HEPA intervention involved 150 min of weekly moderately intense aerobic activity and twice-weekly circuit training. Practical and theoretical physiotherapist support was available the first year, but not the second year. Skeletal muscle biopsies, functional assessments, and mass spectrometry-based proteomics analysis were conducted. Results: Compliance was high the first year but dropped significantly the second year. Functional improvements in strength, endurance, and lower extremity muscle function (TST) were observed after year 1. Proteomics analysis revealed significant enrichment of mitochondrial proteins including COX8A, citrate synthase, M2OM, NDUFA6, NDUFS2, and VDAC3 after year 1, indicating positive muscle adaptations. However, these changes regressed to baseline levels by year 2. Conclusion: HEPA can induce beneficial mitochondrial adaptations in skeletal muscle of individuals with RA. However, insufficient compliance and progression in HEPA exercise load led to a reversal of these adaptations. Continuous support and motivation are crucial for maintaining and progressing exercise levels and muscle health in individuals with RA. Key points • Health-enhancing physical activity (HEPA) can induce beneficial mitochondrial adaptations in the skeletal muscle proteome of individuals with RA .• Positive effects on mitochondrial protein levels aligned with the participants compliance to the HEPA intervention .• Results emphasizes that sustaining and progressing exercise regimen is crucial to maintain beneficial adaptations for individuals with RA .