Models of accelerated sarcopenia: critical pieces for solving the puzzle of age-related muscle atrophy

Abstract

Sarcopenia, the age-related loss of skeletal muscle mass, is a significant public health concern that continues to grow in relevance as the population ages. Certain conditions have the strong potential to coincide with sarcopenia to accelerate the progression of muscle atrophy in older adults. Among these conditions are co-morbid diseases common to older individuals such as cancer, kidney disease, diabetes, and peripheral artery disease. Furthermore, behaviors such as poor nutrition and physical inactivity are well-known to contribute to sarcopenia development. However, we argue that these behaviors are not inherent to the development of sarcopenia but rather accelerate its progression. In the present review, we discuss how these factors affect systemic and cellular mechanisms that contribute to skeletal muscle atrophy. In addition, we describe gaps in the literature concerning the role of these factors in accelerating sarcopenia progression. Elucidating biochemical pathways related to accelerated muscle atrophy may allow for improved discovery of therapeutic treatments related to sarcopenia.

Figure 1

Mechanisms and consequences of sarcopenia placed within the context of the International Classification of Function (ICF) model developed by the World Health Organization. Sarcopenia is influenced by a host of diseases, cell biology and aging, that manifest through direct or indirect physiological consequences. Subsequently the condition contributes to a number of personal, familial, and societal consequences. Sarcopenia mediates activity limitations (i.e. physical limitation & disability) through influences on muscle strength (dynapenia). Dynapenia: the loss in muscle strength and function that partially results from muscle atrophy (Clark and Manini, 2008). Participation in life situations is the ICF language used to describe the ability of individuals to participate in daily societal activities such as going to the grocery store, attending family events, or traveling.

Figure 2

Mechanisms associated with accelerated sarcopenia due to disease conditions and behaviors. Although aging contributes to the presence of these atrophy-related mechanisms, these behaviors and diseases enhance their activity. The figure is interpreted directionally from outer to inner rings (light to dark grey) ultimately leading to myocyte and myofibrillar protein loss. Plus signs (+) indicate upregulation and negative signs (-) equate to downregulation of a specific pathway. The figure represents a step-down approach to how certain disease conditions and behaviors can modulate four of the major mechanistic pathways involved in sarcopenia: apoptosis, proteolysis, regeneration and protein synthesis. This figure is not intended to be exhaustive or detailed (i.e. a signaling pathway) and thus it may be prone to misrepresentation because of the complexity of interactions involved with multidimensional conditions. However, the model is drawn to illustrate the interactions that serve to feed the major pathways that accelerate sarcopenia. These interactions include, but are not limited to changes in: pro-inflammatory cytokines, anabolic hormones, denervation, mitochondrial function and tissue blood perfusion. Some pathways have feed-forward properties where disease etiology exacerbates the condition (e.g. denervation worsens muscle perfusion in PAD). PAD: Peripheral Arterial Disease, CKD: Chronic Kidney Disease.

Figure 3

The accelerated rate of sarcopenia via various behaviors and diseases depicted based on estimates from the literature. Progression of sarcopenia differs based on the age of disease/condition onset [HIV (onset ∼35 years old): 22% greater (Grinspoon et al., 1999), Hypoxic conditions (onset ∼60 years old): 20% greater (Anker et al., 1999; Clyne et al., 1985; Gosselink et al., 1996; Hambrecht et al., 2005; Marquis et al., 2002; McDermott et al., 2007; Regensteiner et al., 1993), Chronic Kidney Disease (onset ∼70 years old): 25% greater (Sakkas et al., 2003), Liver failure (onset ∼70 years old): 15% greater (Lin et al., 2005), Cancer (onset ∼60 years old): 4.5% greater (Tisdale, 2003), poor protein intake (onset ∼60 years old): 13% greater (Houston et al., 2008)and DM (onset ∼60 years old): 30% greater (Park et al., 2009a), and Lifelong resistance exercise (onset ∼25 years old): 7% less. The Figure assumes that the average decline in muscle mass is ∼1.5% per year after the age of 50 years (Lauretani et al., 2003).