The effects of obesity on skeletal muscle regeneration

Abstract

Obesity and metabolic disorders such as type 2 diabetes mellitus are accompanied by increased lipid deposition in adipose and non-adipose tissues including liver, pancreas, heart and skeletal muscle. Recent publications report impaired regenerative capacity of skeletal muscle following injury in obese mice. Although muscle regeneration has not been thoroughly studied in obese and type 2 diabetic humans and mechanisms leading to decreased muscle regeneration in obesity remain elusive, the initial findings point to the possibility that muscle satellite cell function is compromised under conditions of lipid overload. Elevated toxic lipid metabolites and increased pro-inflammatory cytokines as well as insulin and leptin resistance that occur in obese animals may contribute to decreased regenerative capacity of skeletal muscle. In addition, obesity-associated alterations in the metabolic state of skeletal muscle fibers and satellite cells may directly impair the potential for satellite cell-mediated repair. Here we discuss recent studies that expand our understanding of how obesity negatively impacts skeletal muscle maintenance and regeneration.

Keywords: leptin; lipids; lipotoxicity; muscle regeneration; obesity; satellite cells; skeletal muscle; type 2 diabetes.

Figure 1

Major mechanisms linking obesity with impaired muscle regeneration. Obesity is associated with insulin and leptin resistance, elevated circulating and intramuscular fatty acids, diacylglycerols, ceramides and pro-inflammatory cytokines. Following muscle injury, satellite cells (depicted adjacent to muscle on left) are activated, proliferate, differentiate and form myofibers that grow and replace damaged tissue. Impairment of these processes underlies inefficient muscle regeneration in obese rodents. Defective leptin signaling can contribute to decreased satellite cell proliferation and impaired muscle hypertrophy, but the molecular mechanisms are not known. Fatty acids, diacylglycerols (DAG) and ceramides induce apoptosis and decrease myoblast proliferation and differentiation, possibly via activation of myostatin and inhibition of MyoD and myogenin expression and/or activity. Ceramides and pro-inflammatory cytokines inhibit muscle growth in part by inhibiting the IGF-1/Akt /mTOR pathway.