Cancer-associated muscle weakness - From triggers to molecular mechanisms.

Skeletal muscle weakness is a debilitating consequence of many malignancies. Muscle weakness has a negative impact on both patient wellbeing and outcome in a range of cancer types and can be the result of loss of muscle mass (i.e. muscle atrophy, cachexia) and occur independently of muscle atrophy or cachexia. There are multiple cancer specific triggers that can initiate the progression of muscle weakness, including the malignancy itself and the tumour environment, as well as chemotherapy, radiotherapy and malnutrition. This can induce weakness via different routes: 1) impaired intrinsic capacity (i.e., contractile dysfunction and intramuscular impairments in excitation-contraction coupling or crossbridge cycling), 2) neuromuscular disconnection and/or 3) muscle atrophy. The mechanisms that underlie these pathways are a complex interplay of inflammation, autophagy, disrupted protein synthesis/degradation, and mitochondrial dysfunction. The current lack of therapies to treat cancer-associated muscle weakness highlight the critical need for novel interventions (both pharmacological and non-pharmacological) and mechanistic insight. Moreover, most research in the field has placed emphasis on directly improving muscle mass to improve muscle strength. However, accumulating evidence suggests that loss of muscle function precedes atrophy. This review primarily focuses on cancer-associated muscle weakness, independent of cachexia, and provides a solid background on the underlying mechanisms, methodology, current interventions, gaps in knowledge, and limitations of research in the field. Moreover, we have performed a mini-systematic review of recent research into the mechanisms behind muscle weakness in specific cancer types, along with the main pathways implicated.

Identifying Novel Osteoarthritis-Associated Genes in Human Cartilage Using a Systematic Meta-Analysis and a Multi-Source Integrated Network.

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.

Skeletal Muscle Wasting and Its Relationship With Osteoarthritis: a Mini-Review of Mechanisms and Current Interventions.

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. 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.