In chronic heart failure (HF) from systolic cardiac dysfunc-tion, the degree of exercise intolerance is not directly related to the degree of cardiac weakness. 1–5 Somewhat surprisingly symptoms that typify HF, including shortness of breath and fatigue, are often directly related to the abnormalities of the skeletal musculature in HF. Our understanding of the features of skeletal myopathy is evolving as therapy for HF is changing and improving. Understanding the skeletal myopathy of HF is important for 2 reasons:(1) therapies, including heart transplantation, only directed at improving cardiac function, will not immediately and may never improve exercise capacity in HF, and (2) with greater understanding of the mechanisms underlying the skeletal myopathy of HF, specific therapies targeting these abnormalities can be developed.

I will review the features of the skeletal myopathy of HF, as currently understood, based on state-of-the-art research in humans and animal models. I will then examine the mechanisms underlying the skeletal myopathy, which appears not to be unique to HF but are shared by other chronic diseases such as chronic obstructive pulmonary disease (COPD) and chronic renal disease. 3 Specifically, the role of “coordinated adaptation,” an energy-conserving strategy to maximize efficiency in a damaged system, will be examined in the development of the skeletal myopathy in all of these chronic diseases. 6 Further, I will present evidence supporting the concept that sympathetic nerve activation (SNA) initiates and maintains this systemic, coordinated adaptation. Finally, the impact of current and future pharmacological and nonpharmacological therapies will be related to the above pathophysiology of the skeletal myopathy of HF.