Pathogenesis of sarcopenia and the relationship with fat mass: descriptive review

Abstract

Age-associated obesity and muscle atrophy (sarcopenia) are intimately connected and are reciprocally regulated by adipose tissue and skeletal muscle dysfunction. During ageing, adipose inflammation leads to the redistribution of fat to the intra-abdominal area (visceral fat) and fatty infiltrations in skeletal muscles, resulting in decreased overall strength and functionality. Lipids and their derivatives accumulate both within and between muscle cells, inducing mitochondrial dysfunction, disturbing β-oxidation of fatty acids, and enhancing reactive oxygen species (ROS) production, leading to lipotoxicity and insulin resistance, as well as enhanced secretion of some pro-inflammatory cytokines. In turn, these muscle-secreted cytokines may exacerbate adipose tissue atrophy, support chronic low-grade inflammation, and establish a vicious cycle of local hyperlipidaemia, insulin resistance, and inflammation that spreads systemically, thus promoting the development of sarcopenic obesity (SO). We call this the metabaging cycle. Patients with SO show an increased risk of systemic insulin resistance, systemic inflammation, associated chronic diseases, and the subsequent progression to full-blown sarcopenia and even cachexia. Meanwhile in many cardiometabolic diseases, the ostensibly protective effect of obesity in extremely elderly subjects, also known as the 'obesity paradox', could possibly be explained by our theory that many elderly subjects with normal body mass index might actually harbour SO to various degrees, before it progresses to full-blown severe sarcopenia. Our review outlines current knowledge concerning the possible chain of causation between sarcopenia and obesity, proposes a solution to the obesity paradox, and the role of fat mass in ageing.

Keywords: Inflammation; Insulin resistance; Myosteatosis; Obesity; Proto-sarcopenia; Sarcopenia.

Figure 1

The metabaging cycle. (1) during transient hyperlipidaemia after food intake or inactivity, or local hyperlipidaemia due to lipolysis, nearby adipose tissues are driven to expand. (2) Excess lipids are thought to ‘spill over’ and redistribute to other tissues, especially the skeletal muscles. (3) Lipids and their derivatives accumulate both within and between muscle cells (myosteatosis), inducing mitochondrial dysfunction, disturbing β‐oxidation of fatty acids, and enhancing reactive oxygen species (ROS) production, leading to lipotoxicity, which also induces (4) insulin resistance and (5) inflammation. The pro‐inflammatory factors further induce infiltration of macrophages and other immune cells into adipose and muscle, which further secrete a large amount of pro‐inflammatory cytokines and chemokines, thus broadening the local chronic inflammation into a low‐grade systemic inflammaging state in adipose depots and muscles, which further spreads inflammation‐induced insulin resistance and lipid dysfunction. (6) The vicious cycle of local myosteatosis and muscle insulin resistance can now complete a larger vicious cycle leading to reducing lipid uptake and increasing local free fatty acid concentrations, and thus local lipolysis. The resultant local hyperlipidaemia, lipotoxicity, and insulin resistance that triggered the local inflammaging, further worsens the lipid dysfunction and insulin resistance in a spreading vicious cycle that results in sarcopenic obesity. We call this the metabaging cycle.

Figure 2

Resolving the obesity paradox. During ageing, adipose inflammation leads to the redistribution of fat to the intra‐abdominal area (visceral fat) and fatty infiltration into muscle. Intramuscular fat infiltration increases the chances of progression to obesity, which reduced muscular renewal, progressing to pre‐sarcopenia. This synergy between muscle loss (pre‐sarcopenia) and fatty infiltration (myosteatosis) might trigger and aggravate the pathogenesis of sarcopenic obesity (SO), low‐grade inflammation (inflammaging) and systemic insulin resistance. SO patients may appear as ‘normal’ subjects due to the mutual masking effect of sarcopenia and obesity. The vicious cycle of local myosteatosis and muscle insulin resistance can complete a larger vicious cycle leading to increasing lipolysis and local free fatty acid concentrations (the metabaging cycle), thereby worsening and spreading the local hyperlipidaemia. But after a long period of systemic inflammaging, chronic inflammation would exhaust both extant and newly formed adipose depots, leading to the systemic atrophy and wasting observed in cachexia and full‐blown sarcopenia. This suggests that SO may progress to full‐blown sarcopenia in the same way that cachexia develops: systemic inflammation‐induced adipose atrophy, which unmasks and exacerbates the muscle atrophy.