Activation of the dopamine 1 and dopamine 5 receptors increase skeletal muscle mass and force production under non-atrophying and atrophying conditions

Abstract

BackgroundControl of skeletal muscle mass and force production is a complex physiological process involving numerous regulatory systems. Agents that increase skeletal muscle cAMP levels have been shown to modulate skeletal muscle mass and force production. The dopamine 1 receptor and its closely related homolog, the dopamine 5 receptor, are G-protein coupled receptors that are expressed in skeletal muscle and increase cAMP levels when activated. Thus we hypothesize that activation of the dopamine 1 and/or 5 receptor will increase skeletal muscle cAMP levels thereby modulating skeletal muscle mass and force production.MethodsWe treated isolated mouse tibialis anterior (TA) and medial gastrocnemius (MG) muscles in tissue bath with the selective dopamine 1 receptor and dopamine 5 receptor agonist SKF 81297 to determine if activation of skeletal muscle dopamine 1 and dopamine 5 receptors will increase cAMP. We dosed wild-type mice, dopamine 1 receptor knockout mice and dopamine 5 receptor knockout mice undergoing casting-induced disuse atrophy with SKF 81297 to determine if activation of the dopamine 1 and dopamine 5 receptors results in hypertrophy of non-atrophying skeletal muscle and preservation of atrophying skeletal muscle mass and force production.ResultsIn tissue bath, isolated mouse TA and MG muscles responded to SKF 81297 treatment with increased cAMP levels. Treating wild-type mice with SKF 81297 reduced casting-induced TA and MG muscle mass loss in addition to increasing the mass of non-atrophying TA and MG muscles. In dopamine 1 receptor knockout mice, extensor digitorum longus (EDL) and soleus muscle mass and force was not preserved during casting with SKF 81297 treatment, in contrast to significant preservation of casted wild-type mouse EDL and soleus mass and EDL force with SKF 81297 treatment. Dosing dopamine 5 receptor knockout mice with SKF 81297 did not significantly preserve EDL and soleus muscle mass and force although wild-type mouse EDL mass and force was significantly preserved SKF 81297 treatment.ConclusionsThese data demonstrate for the first time that treatment with a dopamine 1/5 receptor agonist results in (1) significant preservation of EDL, TA, MG and soleus muscle mass and EDL muscle force production during periods of atrophy and (2) hypertrophy of TA and MG muscle. These effects appear to be mainly mediated by both the dopamine 1 and dopamine 5 receptors.

Vivo-Morpholinos Induced Transient Knockdown of Physical Activity Related Proteins

“…It has been previously suggested that Drd1 , Glut4 , and Vmat2 are potential candidate genes for the regulation of physical activity [1], [6], [7], [8], [10], [13] with Glut4 in particular, showing a direct effect on activity when over expressed [11]. Thus, we were somewhat surprised that knockdown of both Drd1 and Glut4 simultaneously in soleus (Experiment 3) did not affect activity levels.…”

“…However, the rebound of Vmat2 observed in the soleus (Experiment 1 and 2) and nucleus accumbens (Experiment 2) along with the associated increase in physical activity could provide a potential explanation for the regulation of voluntary physical activity. It has been shown that the dopamine system in skeletal muscle affects muscle force production [8] and in the brain affects reward driven behavior [6]. When mice are given, artificial dopamine there is an associated hyperactivity response [50], [51], [54], [58].…”

“…With only 3.5% of adults meeting the recommended physical activity guidelines [2], physical inactivity is the second leading actual cause of death (∼250,000 cases/year) in the United States [3] with an estimated $507 billion a year in health care costs [1]. Several potential candidate genes associated with the genetic influence on voluntary physical activity have been identified [1], [4], [5], [6], [7], [8], [9], [10], [11] with potential regulatory effects both in the brain and skeletal muscle.…”

“…Of the candidate genes identified, Dopamine Receptor 1 ( Drd1 ; [1], [6], [7], [8], [9]), Glucose Transporter 4 [ Glut4 , aka: Slc2a4 ; 11], and Vesicular Monoamine Transporter 2 ( Vmat2 ; [4], [10], [12], [13]), have been the most widely studied in association with voluntary physical activity. Vmat2 is expressed in the brain and skeletal muscle.…”

“…Another central factor contributing the regulation of physical activity is Drd1 ; high active mice have an under expression of Drd1 which results in a decrease in dopamine turnover in the nucleus accumbens [6] and a suggested increase in reward driven behavior and voluntary physical activity [6], [7]. It has recently been proposed that Drd1 expression in skeletal muscle could have similar effects on physical activity with an increase in D1 receptors ( Drd1 and Drd5 ) in skeletal muscle being associated with an increase in muscle force production and prevention of atrophy [8]. An additional mechanism by which peripheral factors could regulate physical activity is through Glut4 .…”