Endogenous α-calcitonin-gene-related peptide promotes exercise-induced, physiological heart hypertrophy in mice

AimIt is unknown how the heart distinguishes various overloads, such as exercise or hypertension, causing either physiological or pathological hypertrophy. We hypothesize that alpha-calcitonin-gene-related peptide (CGRP), known to be released from contracting skeletal muscles, is key at this remodelling. MethodsThe hypertrophic effect of CGRP was measured in vitro (cultured cardiac myocytes) and in vivo (magnetic resonance imaging) in mice. Exercise performance was assessed by determination of maximum oxygen consumption and time to exhaustion. Cardiac phenotype was defined by transcriptional analysis, cardiac histology and morphometry. Finally, we measured spontaneous activity, body fat content, blood volume, haemoglobin mass and skeletal muscle capillarization and fibre composition. ResultsWhile CGRP exposure yielded larger cultured cardiac myocytes, exercise-induced heart hypertrophy was completely abrogated by treatment with the peptide antagonist CGRP(8-37). Exercise performance was attenuated in CGRP(-/-) mice or CGRP(8-37) treated wild-type mice but improved in animals with higher density of cardiac CGRP receptors (CLR-tg). Spontaneous activity, body fat content, blood volume, haemoglobin mass, muscle capillarization and fibre composition were unaffected, whereas heart index and ventricular myocyte volume were reduced in CGRP(-/-) mice and elevated in CLR-tg. Transcriptional changes seen in CGRP(-/-) (but not CLR-tg) hearts resembled maladaptive cardiac phenotype. ConclusionsAlpha-calcitonin-gene-related peptide released by skeletal muscles during exercise is a hitherto unrecognized effector directing the strained heart into physiological instead of pathological adaptation. Thus, CGRP agonists might be beneficial in heart failure patients.