The gene ANGPTL2 is starting to look like an interesting basis for therapy, something to bump closer to the top of the lengthy list of targets to consider for first generation human gene therapies. In animal studies, lowering the level of protein produced by this gene has been shown to reduce chronic inflammation in older individuals and slow progression towards heart failure. These effects might be mediated through the presence of senescent cells in the cardiovascular system, in that it is these cells that are the primary producers of ANGPTL2. One of the most easily measured consequences of the growing numbers of senescent cells in older tissues is a higher level of inflammation.
Here researchers show that loss of ANGPTL2 can slow the age-related decline in muscle mass that takes place in later life, a condition known as sarcopenia. They also consider cellular senescence to be a plausible mediating mechanism for the detrimental effects of ANGPTL2 when it is present, and certainly there is plenty of evidence to link sarcopenia with chronic inflammation. Raised levels of inflammation and other activities of senescent cells derail the normal processes of tissue maintenance. If this is the case, and ANGPTL2 does cause harm due to increased levels of cellular senescence or increased activity of senescent cells, then senolytic therapies that destroy senescent cells should capture all of the benefits of reduced levels of ANGPTL2, rendering gene therapy approaches redundant in this case. That is a proposition that could be tested in mice now, given the present state of the field.
Sarcopenia is defined as age-related loss of skeletal muscle mass and strength, a condition that worsens subjects' quality of life. Clarification of molecular mechanisms underlying sarcopenia development is important to devise effective approaches to treat this condition. Several lines of evidence support the idea that in skeletal muscle chronic inflammation and reactive oxygen species (ROS) accumulation due to redox imbalance contribute to sarcopenia development, and chronic inflammation in aging skeletal muscle is positively correlated with sarcopenia development in humans and mice.
The pro-inflammatory cytokines interleukin-6 (IL-6) and interleukin-1β (IL-1β) both decrease skeletal muscle mass by causing inflammation and subsequently facilitating muscle proteolysis, ROS accumulation, and growth hormone resistance. Moreover, excess ROS accumulation causes oxidative damage to skeletal muscles, resulting in myofibers loss. Both inflammation and ROS accumulation inactivate "satellite cells", the precursors of skeletal muscle cells, thereby accelerating sarcopenia development.
Previous studies reveal that expression and secretion of angiopoietin-like 2 (ANGPTL2) significantly increase in cells stressed by pathophysiological stimuli, such as hypoxia and senescence-associated secretory phenotype (SASP) factor. Moreover, excess ANGPTL2 signaling is pro-inflammatory in pathological states and contributes to development of aging-associated diseases.
Although ANGPTL2 hyperactivation is associated with age-related diseases, ANGPTL2 function in sarcopenia development remains unknown. Here, we investigated the roles of ANGPTL2 in sarcopenia development using aging mice. We report that ANGPTL2 expression increases in skeletal myocytes of aging mice and that running exercise decreases that expression, suggesting that excess ANGPTL2 signaling in aged skeletal muscular myofibers accelerates sarcopenia development. Moreover, ANGPTL2 deficient mice showed attenuated loss of skeletal muscle by reduced muscular inflammation and ROS accumulation and increased satellite cell activity. To the best of our knowledge, this is the first report showing that ANGPTL2 signaling may accelerate sarcopenia pathologies.