Lack of ß2 -adrenoceptors aggravates heart failure-induced skeletal muscle myopathy in mice.

ABSTRACT

Skeletal myopathy is a hallmark of heart failure (HF) and has been associated with a poor prognosis. HF and other chronic degenerative diseases share a common feature of a stressed system sympathetic hyperactivity. Although beneficial acutely, chronic sympathetic hyperactivity is one of the main triggers of skeletal myopathy in HF. Considering that ß2 -adrenoceptors mediate the activity of sympathetic nervous system in skeletal muscle, we presently evaluated the contribution of ß2 -adrenoceptors for the morphofunctional alterations in skeletal muscle and also for exercise intolerance induced by HF. Male WT and ß2 -adrenoceptor knockout mice on a FVB genetic background (ß2 KO) were submitted to myocardial infarction (MI) or SHAM surgery. Ninety days after MI both WT and ß2 KO mice presented to cardiac dysfunction and remodelling accompanied by significantly increased norepinephrine and epinephrine plasma levels, exercise intolerance, changes towards more glycolytic fibres and vascular rarefaction in plantaris muscle. However, ß2 KO MI mice displayed more pronounced exercise intolerance and skeletal myopathy when compared to WT MI mice. Skeletal muscle atrophy of infarcted ß2 KO mice was paralleled by reduced levels of phosphorylated Akt at Ser 473 while increased levels of proteins related with the ubiquitin--proteasome system, and increased 26S proteasome activity. Taken together, our results suggest that lack of ß2 -adrenoceptors worsen and/or anticipate the skeletal myopathy observed in HF.