Apoptosis in sarcopenia

Today, two interesting articles on the relationship between apoptosis and sarcopenia, the decrease in muscle mass and function that accompanies mammalian aging. Sarcopenia is a major underlying cause of age-related frailty, which in turn has severe impacts on quality of life and the prognosis of other maladies. An understanding of its causes would contribute greatly to therapeutic strategies designed to promote healthy aging. (For further discussion, see Preventing age-related muscle loss.)

The first paper, a primary study by Pistilli et al. on muscle loss in the aging rat, focuses on the extrinsic pathway and TNF-α signaling:

Tumor necrosis factor-alpha (TNF-α) is elevated in the serum as a result of aging and it promotes pro-apoptotic signaling upon binding to the type I TNF receptor. It is not known if activation of this apoptotic pathway contributes to the well-documented age-associated decline in muscle mass (i.e. sarcopenia). We tested the hypothesis that skeletal muscles from aged rodents would exhibit elevations in markers involved in the extrinsic apoptotic pathway when compared to muscles from young adult rodents, thereby contributing to an increased incidence of nuclear apoptosis in these muscles. … These data demonstrate that pro-apoptotic signaling downstream of the TNF receptor is active in aged muscles. Furthermore, our data extend the previous demonstration that type II fibers are preferentially affected by aging and support the hypothesis that type II fiber containing skeletal muscles may be more susceptible to muscle mass loses via the extrinsic apoptotic pathway.

The second paper, a review of the subject by Marzetti and Leeuwenburgh, focuses more on the intrinsic pathway and the role of mitochondria in myocyte apoptosis:

The loss of muscle mass and strength with aging, also referred to as sarcopenia of aging, is a highly prevalent condition among older adults and predicts several adverse outcomes, including disability, institutionalization and mortality. Although the exact mechanisms underlying sarcopenia are far to be unveiled, accumulating preclinical evidence suggests that an age-related acceleration of myocytes loss via apoptosis might represent a key mechanism driving the onset and progression of muscle loss. Furthermore, increased levels of apoptosis have also been reported in old rats undergoing acute muscle atrophy subsequent to muscle unloading, a condition that mimics the muscle loss observed during prolonged bed rest. Notably, preliminary evidence seems to confirm a causative role for apoptosis in age-related muscle loss in human subjects. Several signaling pathways of skeletal muscle apoptosis are currently under intense investigation, with a particular focus on the role played by mitochondria. …

The two pathways to apoptosis (extrinsic vs. intrinsic) are biochemically distinct, and the authors do focus on slightly different experimental models (baseline muscle loss in active animals vs. muscle that has been “unloaded” and is therefore in a state of enforced inactivity), but there’s no reason why both couldn’t be acting throughout a tissue over the course of the aging process.