Mechanical signals protect stem cell lineage selection, preserving the bone and muscle phenotypes in obesity

Abstract

The incidence of obesity is rapidly rising, increasing morbidity and mortality rates worldwide. Associated comorbidities include type 2 diabetes, heart disease, fatty liver disease, and cancer. The impact of excess fat on musculoskeletal health is still unclear, although it is associated with increased fracture risk and a decline in muscular function. The complexity of obesity makes understanding the etiology of bone and muscle abnormalities difficult. Exercise is an effective and commonly prescribed nonpharmacological treatment option, but it can be difficult or unsafe for the frail, elderly, and morbidly obese. Exercise alternatives, such as low-intensity vibration (LIV), have potential for improving musculoskeletal health, particularly in conditions with excess fat. LIV has been shown to influence bone marrow mesenchymal stem cell differentiation toward higher-order tissues (i.e., bone) and away from fat. While the exact mechanisms are not fully understood, recent studies utilizing LIV both at the bench and in the clinic have demonstrated some efficacy. Here, we discuss the current literature investigating the effects of obesity on bone, muscle, and bone marrow and how exercise and LIV can be used as effective treatments for combating the negative effects in the presence of excess fat.

Keywords: diabetes; exercise; musculoskeletal; osteoporosis; vibration.

Figure 1

Schematic (adapted from Ref. 49) depicts the bone marrow cellular niche (right) and muscle cellular niche (left). The bone marrow is a dynamic heterogeneous environment and home to mesenchymal and hematopoietic stem cells. Mesenchymal stem cells regulate bone and fat systems in the marrow and support the hematopoietic niche. Hematopoietic stem cells regulate blood and immune cells, which can be compromised by obesity. The skeletal muscle microenvironment comprises multinucleated myofibers and stem cells, including satellite cells, mesenchymal progenitors, and fibro/adipogenic progenitors. Obesity results in increased intramyocellular lipid accumulation within myofibers and increased local adipocytes, likely through mesenchymal or fibro/adipogenic progenitor differentiation. This change is paralleled in the marrow, where increased marrow adipose tissue is characteristic of conditions with excess adiposity. Maintaining healthy levels of fat in bone and muscle may be achieved through mechanical stimulation intervention and biasing stem cell differentiation away from adipogenesis.