Aerobic Exercise and Pharmacological Therapies for Skeletal Myopathy in Heart Failure: Similarities and Differences

Figure 2

Direct and indirect effects of Ang II on skeletal muscle mass. The direct effects of angiotensin II (Ang II) in skeletal muscle include increases ROS production via AT₁ receptor and NADPH oxidase activation, which results in activation of UPS and protein degradation. The indirect effects of systemic Ang II are mediated by increased ROS induced caspase-3 besides enhanced TNF-α and myostatin levels. Ang II also directly suppresses protein synthesis via AT₁ receptor inhibiting PI3K and by indirect mechanisms via Ang II attenuating IGF-I while increasing myostatin levels. Ang II-induced muscle wasting can also result from impaired muscle regeneration by Ang II-induced inhibition of skeletal muscle stem (satellite) cell proliferation and function. It is important to highlight that these multiple direct and indirect mechanisms involving Ang II-induced muscle wasting are potential mediators of cardiac cachexia. PI3K: phosphoinositide 3-kinase, Akt: protein kinase B, UPS: ubiquitin-proteasome system, mTOR: mammalian target of rapamycin, TNF-α: tumor necrosis factor-alpha, IGF-I: insulin-like growth factor-I, ATP: adenosine triphosphate, AMP: adenosine monophosphate, AMPK: AMP-activated protein kinase, NADPH oxidase: nicotinamide adenine dinucleotide phosphate-oxidase, and ROS: reactive oxygen species.