Corticotropin releasing factor 2 receptor agonists reduce the denervation-induced loss of rat skeletal muscle mass and force and increase non-atrophying skeletal muscle mass and force.
Of the two corticotropin releasing factor receptors known, corticotrophin releasing factor 2 receptor (CRF2R) is expressed in skeletal muscle. The function of this receptor in skeletal muscle is at present unknown. In order to better understand the role of the CRF2R in skeletal muscle, we treated rats with CRF2R agonists and evaluated the effect of these agents on normal and denervated muscle mass. Rats treated with the non-selective CRFR agonist, sauvagine, did not demonstrate any significant and consistent change in non-denervated and denervated fast twitch [tibialis anterior (TA) or extensor digitorum longus (EDL)] or slow/mixed twitch [medial gastrocnemius (MG) or soleus] fiber muscle mass. In adrenalectomized rats, sauvagine treatment resulted in no significant and consistent change in non-denervated fast or slow/mixed twitch fiber muscles but did cause a significant and consistent increase in denervated fast twitch (TA and EDL) but not slow/mixed twitch muscle mass. Interestingly adrenalectomy had no effect on the degree of muscle atrophy. Rats treated with the CRF2R selective agonist urocortin 2 demonstrated an increase in non-denervated and denervated fast and slow/mix twitch fiber muscle mass. The urocortin 2 induced increase in muscle mass was accompanied by an increase in muscle fiber cross-sectional area and muscle absolute force. These studies demonstrated that activation of the CRF2R decreased the level of skeletal muscle mass, force, and myocyte cross-sectional area loss resulting from sciatic nerve damage and increased the mass, force and myocyte cross-sectional area of normal (non-atrophying) skeletal muscle. In addition, we also observed that removal of the adrenals increased the effectiveness of the non-selective CRFR agonists sauvagine, presumably via the removal of the pro-atrophy influence of adrenal produced corticosteroids. These results demonstrate that pharmacological modulation of the CRF2R may be a viable method to treat skeletal muscle atrophy.
Hinkle
R T
RT
Research Division, Procter & Gamble Pharmaceuticals, Health care Research Center, 8700, Mason-Montgomery Road, Mason, OH 45040, USA.
Donnelly
E
E
Cody
D B
DB
Bauer
M B
MB
Sheldon
R J
RJ
Isfort
R J
RJ
D029845:Amphibian Proteins; D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology*; D000242:Cyclic AMP / Q000737:chemistry; D005260:Female; D032342:Muscle Cells / Q000187:drug effects / Q000502:physiology; D009121:Muscle Denervation; D018482:Muscle, Skeletal / Q000187:drug effects / Q000502:physiology*; D036361:Peptide Hormones; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000819:agonists* / Q000187:drug effects / Q000502:physiology; D054832:Urocortins
D029845:Amphibian Proteins; D036361:Peptide Hormones; D010455:Peptides; D018019:Receptors, Corticotropin-Releasing Hormone; D054832:Urocortins; C499434:corticotropin-releasing factor receptor type 2a, rat; C025727:sauvagine; D003346:Corticotropin-Releasing Hormone; D000242:Cyclic AMP