Age-related and disease-related muscle loss: the effect of diabetes, obesity, and other diseases

Abstract

The term sarcopenia refers to the loss of muscle mass that occurs with ageing. On the basis of study results showing that muscle mass is only moderately related to functional outcomes, international working groups have proposed that loss of muscle strength or physical function should also be included in the definition. Irrespective of how sarcopenia is defined, both low muscle mass and poor muscle strength are clearly highly prevalent and important risk factors for disability and potentially mortality in individuals as they age. Many chronic diseases, in addition to ageing, could also accelerate decrease of muscle mass and strength, and this effect could be a main underlying mechanism by which chronic diseases cause physical disability. In this Review, we address both age-related and disease-related muscle loss, with a focus on diabetes and obesity but including other disease states, and potential common mechanisms and treatments. Development of treatments for age-related and disease-related muscle loss might improve active life expectancy in older people, and lead to substantial health-care savings and improved quality of life.

Figure 1. Pathways of accelerated muscle loss in type 2 diabetes

The presence of insulin resistance in type 2 diabetes leads to autophagy, muscle protein degradation (ie, via the ubiquitin-proteasome proteolytic pathway), and mitochondrial dysfunction (solid line). These processes ultimately lead to loss of muscle mass or muscle strength, or both. A cycle is created in which loss of muscle mass and muscle strength lead to decreased surface area for glucose transport and potential exacerbation of insulin resistance (dotted line). The progression of mitochondrial dysfunction might also worsen insulin resistance (dotted line). Increasing severity of insulin resistance then stimulates pathways resulting in accelerated loss of muscle, and the cycle starts again.^-

Figure 2. Development of sarcopenic obesity

Obesity triggers a cascade of events including increased adipocyte size and number of macrophages, more pro-inflammatory senescent cells in adipose tissue, increased inflammatory markers, reactive oxygen species, insulin resistance, and leptin along with lowered adiponectin, and, ultimately, loss of muscle mass and strength disproportionate to relatively greater body size. The skeletal muscle, or engine, is insufficient to transport the obese individual and leads to the development of sarcopenia. Sarcopenia, in turn, is associated with physical inactivity, reduced energy expenditure, and possibly other processes that increase obesity. Either sarcopenia or obesity could be the initial step in the development of sarcopenic obesity, creating a vicious cycle.^,-

Figure 3. Potential mechanisms of age-related and disease-related muscle loss

An almost-unexplored hypothesis is that chronic diseases, many of which increase in prevalence with age, contribute to the age-related decrease in muscle mass and strength observed in many older individuals (dashed arrow). The presence of either old age or a specific disease, or both, has been linked with increasing pro-inflammatory cytokines, oxidative stress, catabolic hormones, and denervation; and decreasing vascular perfusion, aminoacid bioavailability, and anabolic hormones. These mechanisms could affect skeletal muscle characteristics that have been associated with sarcopenia, including increased myocyte apoptosis, protein degradation, myofibre necrosis, fibre-type grouping, and intramyocellular lipids; or decreased protein synthesis, motor neurone function, mitochondrial biogenesis, and satellite cell regeneration. GH=growth hormone. PAD=peripheral arterial disease. CHF=congestive heart failure. CKD=chronic kidney disease. COPD=chronic obstructive pulmonary disease.