Effects of weight loss and leptin on skeletal muscle in human subjects

Abstract

Maintenance of a 10% or greater reduced body weight results in decreases in the energy cost of low levels of physical activity beyond those attributable to the altered body weight. These changes in nonresting energy expenditure are due mainly to increased skeletal muscle work efficiency following weight loss and are reversed by the administration of the adipocyte-derived hormone leptin. We have also shown previously that the maintenance of a reduced weight is accompanied by a decrease in ratio of glycolytic (phosphofructokinase) to oxidative (cytochrome c oxidase) activity in vastus lateralis muscle that would suggest an increase in the relative expression of the myosin heavy chain I (MHC I) isoform. We performed analyses of vastus lateralis muscle needle biopsy samples to determine whether maintenance of an altered body weight was associated with changes in skeletal muscle metabolic properties as well as mRNA expression of different isoforms of the MHC and sarcoplasmic endoplasmic reticular Ca(2+)-dependent ATPase (SERCA) in subjects studied before weight loss and then again after losing 10% of their initial weight and receiving twice daily injections of either placebo or replacement leptin in a single blind crossover design. We found that the maintenance of a reduced body weight was associated with significant increases in the relative gene expression of MHC I mRNA that was reversed by the administration of leptin as well as an increase in the expression of SERCA2 that was not significantly affected by leptin. Leptin administration also resulted in a significant increase in the expression of the less MHC IIx isoform compared with subjects receiving placebo. These findings are consistent with the leptin-reversible increase in skeletal muscle chemomechanical work efficiency and decrease in the ratio of glycolytic/oxidative enzyme activities observed in subjects following dietary weight loss.

Fig. 1.

Schematic of protocol. Studies, including assessment of circulating leptin (lep) concentrations, energy expenditure, body composition, and skeletal muscle biopsy, are identical at each testing period.

Fig. 2.

Effects of weight loss and replacement administration of leptin on skeletal muscle work efficiency (calories expended per minute per watt of power generated during bicycle ergometry) and activity of glycolytic [phosphofructokinase (PFK)] and fatty acid oxidative [cytochrome c oxidase (COX) and hydroxyacyl CoA dehydrogenase (HADH)] in the vastus lateralis muscle of 10 subjects. Shown is the change from the initial value at the initial weight prior to weight loss in response to maintaining 10% body weight reduction with or without leptin treatment for ∼5 wk. *P < 0.05 compared with 0 and to Wt_−10%leptin.

Fig. 3.

Effects of weight loss and replacement administration of leptin on (myosin heavy chain (MHC) mRNA isoform expression, as well as sarcoplasmic reticulum Ca²⁺-ATPase 1 (SERCA1) and -2 mRNA gene expression in the vastus lateralis muscle of 10 subjects. Shown is the change from the initial value at the initial weight prior to weight loss in response to maintaining 10% body weight reduction with or without leptin treatment for ∼5 wk. *P < 0.05 compared with 0 and to Wt_−10%leptin, †P < 0.05 compared with Wt_{−10%placebo}; §P < 0.05 compared with 0 and to Wt_{−10%placebo}.