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Introduction/Overview

Skeletal muscle plays an important role in regulating in metabolic regulation and glycemic control. The modulation of metabolism and glycemic control by the endocannabinoid system (ECS) may be mediated, in part, by effects on skeletal muscle.^{1, 2} Cannabinoid receptor type 1 (CB₁ receptor) mRNA is expressed in skeletal muscle in mice.³

Energy Balance and Metabolic Regulation

Peripheral Metabolic Regulation: Role of the ECS

The ECS may modulate energy expenditure and substrate metabolism through its actions on skeletal muscle.¹ This is consistent with data from a study conducted in genetically obese mice, which showed that the CB₁ receptor antagonist SR141716 increased basal oxygen consumption and increased glucose uptake from isolated soleus muscle.²

Implications

Currently, data on the effects of the ECS on skeletal muscle are less extensive than data collected on other tissues and organs. Recent evidence indicates, however, that blockade of CB₁ receptors may exert direct effects on skeletal muscle that modulate energy homeostasis.^{1, 2}

Glucose Homeostasis

Glycemic Control and Type 2 Diabetes Mellitus: Role of the ECS

The modulation of glycemic control by the ECS may be mediated, in part, by effects on skeletal muscle. Liu et al showed that the rate of glucose uptake by isolated soleus muscle was significantly increased in mice treated for 7 days with SR141716 compared with control mice (Figure 1).² However, it is unclear whether this effect was independent of changes in body weight. Pagotto et al showed that expression of CB₁ receptor mRNA in soleus muscle from dietary-induced obese mice was increased compared with soleus muscle from lean control mice.³ Additional studies are needed to determine the relevance of this observation to the impaired glucose uptake by muscle found in experimental models of insulin resistance.

Implications

The insulin sensitivity of skeletal muscle plays a critical role in regulating glycemic control. Limited preclinical data indicate that CB₁ receptors are expressed in skeletal muscle and CB₁ receptor blockade may enhance glucose uptake.^{2, 3} Although speculative, the clinical implications of these data are that CB₁ receptor blockade may have therapeutic utility for increasing insulin sensitivity in type 2 diabetes and other insulin-resistant states.

Figures

Figure 1. CB₁ receptor blockade enhances glucose uptake in isolated soleus muscle. Genetically obese (Lep^ob/Lep^ob) mice received once daily intraperitoneal injection of SR141716 (10 mg/kg) or control (0.1% Tween 80 in saline; 2 mL/kg) for 7 days. The rate of glucose uptake was measured by the formation of [³H]2-deoxyglucose-6-phosphate in isolated soleus muscle. From Liu YL, Connolly IP, Wilson CA, Stock MJ.²

References

1. Cota D, Woods S. The role of the endocannabinoid system in the regulation of energy homeostasis. Curr Opin Endocrinol Diabetes. 2005;12:338-351.
2. Liu YL, Connoley IP, Wilson CA, Stock MJ. Effects of the cannabinoid CB₁ receptor antagonist SR141716 on oxygen consumption and soleus muscle glucose uptake in Lep(ob)/Lep(ob) mice. Int J Obes (Lond). Feb 2005;29(2):183-187.
3. Pagotto U, Marsicano G, Cota D, Lutz B, Pasquali R. The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocr Rev. Feb 2006;27(1):73-100.