Increased energy expenditure and leptin sensitivity account for low fat mass in myostatin-deficient mice

Abstract

Choi SJ, Yablonka-Reuveni Z, Kaiyala KJ, Ogimoto K, Schwartz MW, Wisse BE. Increased energy expenditure and leptin sensitivity account for low fat mass in myostatin-deficient mice. Am J Physiol Endocrinol Metab 300: E1031-E1037, 2011. First published March 22, 2011; doi:10.1152/ajpendo.00656.2010.-Myostatin deficiency causes dramatically increased skeletal muscle mass and reduced fat mass. Previously, myostatin-deficient mice were reported to have unexpectedly low total energy expenditure (EE) after normalizing to body mass, and thus, a metabolic cause for low fat mass was discounted. To clarify how myostatin deficiency affects the control of body fat mass and energy balance, we compared rates of oxygen consumption, body composition, and food intake in young myostatindeficient mice relative to wild-type (WT) and heterozygous (HET) controls. We report that after adjusting for total body mass using regression analysis, young myostatin-deficient mice display significantly increased EE relative to both WT (ϩ0.81 Ϯ 0.28 kcal/day, P ϭ 0.004) and HET controls (ϩ0.92 Ϯ 0.31 kcal/day, P ϭ 0.005). Since food intake was not different between groups, increased EE likely accounts for the reduced body fat mass (KO: 8.8 Ϯ 1.1% vs. WT: 14.5 Ϯ 1.3%, P ϭ 0.003) and circulating leptin levels (KO: 0.7 Ϯ 0.2 ng/ml vs. WT: 1.9 Ϯ 0.3 ng/ml, P ϭ 0.008). Interestingly, the observed increase in adjusted EE in myostatin-deficient mice occurred despite dramatically reduced ambulatory activity levels (Ϫ50% vs. WT, P Ͻ 0.05). The absence of hyperphagia together with increased EE in myostatin-deficient mice suggests that increased leptin sensitivity may contribute to their lean phenotype. Indeed, leptin-induced anorexia (KO: Ϫ17 Ϯ 1.2% vs. WT: Ϫ5 Ϯ 0.3%) and weight loss (KO: Ϫ2.2 Ϯ 0.2 g vs. WT: Ϫ1.6 Ϯ 0.1, P Ͻ 0.05) were increased in myostatin-deficient mice compared with WT controls. We conclude that increased EE, together with increased leptin sensitivity, contributes to low fat mass in mice lacking myostatin. energy balance; locomotor activity; body fat; insulin sensitivity MYOSTATIN, a member of the transforming growth factor-␤ family, is a paracrine factor that regulates skeletal muscle size and growth by favoring muscle atrophy and inhibiting anabolic signaling (12, 15). In mice (22) and humans (30), homozygous loss-of-function mutation of the myostatin gene causes a phenotype characterized by dramatic, whole body skeletal muscle hypertrophy and hyperplasia. Initial characterization of the energy homeostasis phenotype of myostatin-null mice revealed unexpected findings, suggesting a role for myostatin in the control of energy balance beyond its effect on skeletal muscle. Mature myostatin-null mice were found to have reduced body fat accumulation with age (23). Because energy expenditure (EE; normalized to body weight or lean body mass) in these animals was decreased relative to wild-type (WT) controls, suggestive of increased metabolic efficiency, the low-body fat phenotype remained unexplained (11, 23). A subsequent, extensive analysi...

Increased body condition score through increased lean muscle, but not fat deposition, is associated with reduced reproductive response to oestrus induction in beef cows

“…Cattle affected by either of these mutations have 20% to 25% more muscle (Arthur, 1995;, a condition in cattle known as double muscling. In addition, myostatin is also expressed in the adipose tissue where it increases fatty acid oxidation (Choi et al, 2011;Zhang et al, 2012). Hence, animals deficient in myostatin are very muscular and have low fat deposits, resulting in a high muscle to fat ratio (Clinquart et al, 1995;Choi et al, 2011), similar to the animal model presented in this study.…”

“…In addition, myostatin is also expressed in the adipose tissue where it increases fatty acid oxidation (Choi et al, 2011;Zhang et al, 2012). Hence, animals deficient in myostatin are very muscular and have low fat deposits, resulting in a high muscle to fat ratio (Clinquart et al, 1995;Choi et al, 2011), similar to the animal model presented in this study. Historically, cattle carrying the mutation are known to have poor reproductive performance, including age at first calving and calving interval than the non-mutant cows from the same breed (Hanset et al, 1989;Arthur, 1995).…”

Anti-myostatin antibody increases muscle mass and strength and improves insulin sensitivity in old mice

“…Increased skeletal muscle mass has been associated with increased whole-body energy expenditure. In particular, myostatin knockout mice with marked skeletal muscle hypertrophy displayed increased energy expenditure (16,17). To investigate whether myostatin inhibition would increase wholebody metabolism, we performed metabolic cage studies on mice treated with vehicle or ATA 842.…”

The aging myostatin null phenotype: reduced adiposity, cardiac hypertrophy, enhanced cardiac stress response, and sexual dimorphism

“…In fact, myostatin is expressed at low levels in adipose tissue and has been hypothesized to stimulate or inhibit adipogenesis (Rodgers & Garikipati 2008). However, feed intake is normal in Mstn K/K mice despite a higher total energy expenditure (McPherron & Lee 2002, Choi et al 2011. Guo et al (2009) determined that myostatin attenuation in skeletal muscle, but not adipose tissue, decreases fat mass and improves glucose homeostasis via the diversion of carbohydrates away from adipose stores and into muscle.…”