Written by justis berg
27 June 2011

Catecholamines Reduce Muscle Tissue Breakdown

 

The sympathetic nervous system utilizes two major chemical-signaling molecules: epinephrine (adrenaline) that is secreted directly into the blood from the adrenal gland, and norepinephrine (noradrenaline) that is the major neurotransmitter produced and released from peripheral sympathetic neurons, which are distributed widely to different tissues and are associated with blood vessels. It is well-known that most of the metabolic actions of the sympathetic nervous system in several tissues are exerted through a beta-receptor-mediated increase in intracellular cyclic AMP. There are three types of beta-receptors in most human cells— beta-1 (B1), beta-2 (B2), and beta-3 (B3) receptors.

Βeta-receptors are found on just about every cell in the body except for red blood cells. B1 receptors are the dominant receptor type in the heart and other locations (i.e., salivary glands). However, the heart also contains a significant portion of B2 receptors. B2 receptors are found in the bronchioles of the lung (they cause vasodilatation), the wall muscles of the bladder, the heart, and last but not least, skeletal muscle.

B3 receptors are expressed primarily in adipose tissue, where they regulate energy metabolism and thermogenesis (turning fat into heat and energy), especially in response to norepinephrine.1 Catecholamines have been discussed mostly for their potent effect on fat loss. Bodybuilders often use clenbuterol a few weeks before competition because it stimulates lipolysis and thermogenesis, but it is also highly anabolic at high dosages. New research reports that catecholamines also have a potent effect on reducing muscle tissue breakdown.

Physiological Role of Catecholamines

Historically, the physiological role of the sympathetic nervous system is related to a ‘fight or flight’ response that prepares a person’s ability to cope with a stressful response. Catecholamines have a diverse number of actions in the human body, including:

• Decrease the uptake of glucose in muscle tissue, partly through an inhibition of insulin secretion, thereby stimulating glycogenolysis.

• Increase the diet-induced thermogenesis in brown adipose tissue.

• Increase substrate oxidation (fatty acid) in skeletal muscle, and having a well-known stimulatory effect on white adipose tissue lipolysis (fat burning).

• Having a marked effect on protein metabolism in skeletal muscle. Numerous studies have shown that B2-adrenergic agonists, such as clenbuterol and cimaterol, induce hypertrophy of skeletal muscle in livestock and humans.

Catecholamines Reduce Muscle Tissue Breakdown

B2-adrenergic agonists, such as clenbuterol and cimaterol, have a well-known effect on increasing muscle mass, but new research has shown that increasing catecholamines can also provide potent anti-catabolic actions. Take a look at a couple of neat studies that examine the anti-catabolic actions of catecholamines:

• In order to investigate the physiological role of catecholamines in the control of protein breakdown in skeletal muscles, researchers treated animals with guanethidine for a few days. Guanethidine has been shown to produce a selective blockade of norepinephrine release from peripheral nerves. Guanethidine treatment induces a drastic 90 percent reduction in norepinephrine content of soleus (type I fibers) muscles and a 40-80 percent reduction in plasma levels of norepinephrine and epinephrine.

After two days of guanethidine treatment, there was a 20 percent increase in the rate of protein breakdown in type I fibers. Because this early rise in the protein breakdown occurred without a concomitant change in the plasma levels of other hormones, it was interpreted to be a direct consequence of the depletion of muscle norepinephrine and/or of the reduction in plasma catecholamine concentration induced by guanethidine treatment. Also, the acute increase in muscle tissue breakdown after catecholamine blockade suggested an inhibitory effect on muscle tissue breakdown by catecholamines.2

• Other studies found that epinephrine and norepinephrine, when added to skeletal muscle cell cultures, reduce the rate of protein degradation in normal, fast, and slow-twitch fibers by approximately 15-20 percent.3 This view is consistent with the finding that infusion of epinephrine in humans induces a rapid and similar 20 percent decrease in protein degradation.4

• It has also been shown that the infusion of epinephrine in humans and animals induces a rapid decrease in the activity and gene expression of enzymes involved in muscle protein breakdown.5 Catecholamines exert an acute effect on skeletal muscle protein metabolism, reducing proteolysis. This anabolic effect of the sympathetic nervous system can be interpreted as a mechanism to spare muscle protein during catabolism.

• One study documented that the inhibitory effect of skeletal muscle tissue breakdown is mediated by B2-adrenoceptors. For example, the oral administration of ICI 118,551, a selective B2-adrenoceptor antagonist (blocks the actions of catecholamines), was found to increase muscle tissue breakdown.6 Recent experiments strongly support this hypothesis by demonstrating that the anti-catabolic effect of epinephrine in muscle was completely suppressed by propranolol and by ICI 118,551, blocking the actions of catecholamines on the beta-receptor.7 Clenbuterol on the hand induced a dose-dependent inhibition of protein breakdown that was also prevented by ICI 118,551 (a beta-receptor antagonist) in muscles.8

 

How Do Catecholamines Reduce Muscle Tissue Breakdown?

When you write for MD, you can’t just say something without describing the scientific mechanisms that support your claims. There is a nasty enzyme called calpain that initiates myofibrillar protein breakdown. It appears that calpains are responsible for increasing myofibrillar protein breakdown.8 Studies indicate that epinephrine secreted by the adrenal medulla and norepinephrine released from adrenergic terminals have inhibitory effects on Ca2+ dependent protein breakdown by increasing calpastatin levels. Calpastatin is an endogenous inhibitor of calpain. Recent findings showing that calpastatin overexpression results in skeletal muscle hypertrophy9 and protects mice against atrophy10 provide evidence that calpastatin is also involved in the control of normal skeletal muscle protein turnover. There have been many other mechanisms proposed as to why catecholamines can reduce muscle tissue breakdown, but I didn’t want to turn this article into a biology textbook.

 

Key Points:

• Catecholamines can preserve muscle tissue breakdown.

• Drugs that block the actions of catecholamines can increase muscle tissue breakdown.

• Catecholamines reduce the activity of calpain, an initiator of muscle tissue breakdown.

• Catecholamines increase calpastatin, which is an endogenous inhibitor of calpain. Recent findings showing that calpastatin overexpression results in skeletal muscle hypertrophy and protects against atrophy.

 

References:

1. Mersmann HJ. Overview of the effects of beta-adrenergic receptor agonists on animal growth including mechanisms of action. J Anim Sci, 1998 Jan;76(1):160-72.

2. Navegantes LC, Resano NM, Migliorini RH, Kettelhut IC. Effect of guanethidine-induced adrenergic blockade on the different proteolytic systems in rat skeletal muscle. Am J Physiol, 1999; 277: E883-E889.

3. Navegantes LC, Resano NM, Migliorini RH, Kettelhut IC. Role of adrenoceptors and cAMP on the catecholamine induced inhibition of proteolysis in rat skeletal muscle. Am J Physiol Endocrinol Metab, 2000; 279: E663-E668.

4. Shamoon H, Jacob R, Sherwin RS. Epinephrine-induced hypoaminoacidemia in normal and diabetic human subjects: effect of beta blockade. Diabetes, 1980; 29: 875-881.

5. Viguerie N, Clement K, Barbe P, Courtine M, Benis A, Larrouy D, et al. In vivo epinephrine-mediated regulation of gene expression in human skeletal muscle. J Clin Endocrinol Metab, 2004; 89: 2000-2014.

6. Choo JJ, Horan MA, Little RA, Rothwell NJ. Anabolic effects of clenbuterol on skeletal muscle are mediated by beta 2- adrenoceptor activation. Am J Physiol, 1992; 263: E50-E56.

7. Navegantes LC, Resano NM, Migliorini RH, Kettelhut IC. Effect of guanethidine-induced adrenergic blockade on the different proteolytic systems in rat skeletal muscle. Am J Physiol, 1999; 277: E883-E889.

8. Navegantes LC, Resano NM, Migliorini RH, Kettelhut IC. Catecholamines inhibit Ca2+-dependent proteolysis in rat skeletal muscle through beta(2)-adrenoceptors and cAMP. Am J Physiol Endocrinol Metab, 2001; 281: E449-E454.

9. Otani K, Han DH, Ford EL, Garcia-Roves PM, Ye H, Horikawa Y, et al. Calpain system regulates muscle mass and glucose transporter GLUT4 turnover. J Biol Chem, 2004; 279: 20915-20920.

10. Tidball JG, Spencer MJ. Expression of a calpastatin transgene slows muscle wasting and obviates changes in myosin isoform expression during murine muscle disuse. J Physiol, 2002; 545: 819-828.