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खुला एक्सेस

अमूर्त

Why Age Matters: Inflammation, Cancer and Hormones in the Development of Sarcopenia

Saul D, Schilling AF, Kosinsky RL

In an aging population, the decline in muscle mass and strength in combination with a high prevalence of osteoporosis and cancer leads to a multitude of clinical manifestations. In the recent years, mouse models of wasting in cancer and inflammation, including xenograft, genetic and chemically induced models, allowed to uncover several key mechanisms underlying muscle loss. These include inflammation, hormone alterations and deregulated protein degradation. Inflammation is associated with increased expression of tumor necrosis factor α (TNF-α), nuclear factor κB (NF-κB), and interleukin (IL)-6 and is therefore linked to inflammatory bowel diseases or chronic obstructive pulmonary disease (COPD). Moreover, active NF-κB signaling and IL-6 secretion commonly occurs in malignancies and cancer-induced cachexia. The ubiquitin proteasome-mediated degradation of proteins represents a second pathway underlying sarcopenia and is partially initiated by inflammatory signaling. Consequently, increased levels of the E3 ligases Muscle RING-Finger Protein-1 (MuRF1), Atrogin-1/Muscle Atrophy F-box (MAFbx), and tumor necrosis factor α receptor adaptor protein 6 (TRAF6) are associated with high rates of protein degradation. Furthermore, hormonal alterations, such as the aging-related decline of growth hormone (GH) and insulin-like growth factor 1 (IGF-1), lead to a reduction of muscle mass.

Interestingly, experimental targeting of several of those sarcopenia-associated factors in vivo resulted in a rescue of muscle mass and function. While therapeutic options nowadays still need to be evaluated regarding their clinical practicability, IL-6 antibodies, inhibition of cyclooxygenases and inhibitors of myostatin appear promising.