Mechanism of ICU-acquired weakness: muscle contractility in critical illness

Abstract

Weakness is common after an episode of critical illness and its associated disability may persist for years, with significant negative impact on the survivor [1]. Strength depends on both the presence and normal function of skeletal muscle, so that either muscle wasting or impaired contractility (muscle-specific force) can induce weakness. This is best appreciated in the gerontology literature where sarcopenia, the concept of which has evolved from simple muscle wasting to loss of muscle mass and function, and dynapenia (loss of strength and power not necessarily associated with loss of muscle mass) are identified and considered separately because they are not synonymous [2]. In aging, the decline in strength exceeds the loss of muscle mass and this is attributed to changes throughout the neuroaxis including those occurring at the peripheral nerve in addition to muscle. Muscle unloading/inactivity in animal models promotes a loss of contractile proteins that exceeds the loss in muscle cell size, resulting in decreased myocyte-specific force [3] and in young adults muscle atrophied by immobilization may recover to regain mass but not strength, reinforcing the notion that, like the dynapenia of aging, muscle strength and mass may be discordant. A pilot study of critical illness-associated weakness also suggests this holds true [4]. Therefore, studies evaluating ICU-acquired weakness (ICUAW) should ensure complete assessment for peripheral neuropathy, neuromuscular junction dysfunction in addition to evaluation for myopathy-loss of muscle mass and deficiency of intrinsic contractility. Although the clinical phenotype may be weakness, the relative contributions of underlying processes and cellular and molecular mechanisms may be very different. This review will focus on the impairment of muscle contractility in critical illness and discuss the responsible muscle-derived cellular and molecular mechanisms.If present, critical illness polyneuropathy or neuromuscular blockade will decrease the force-generating capacity of muscle in the ICU patient. Similarly, myonecrosis and/or altered muscle composition will decrease musclespecific force. Even in the absence of these phenomena cellular signalling within the intact muscle fibers of critically ill patients can impede contractile function directly, with or without concurrent induction of changes in muscle size/mass, at least in the short term. Primary muscle contributions to impaired contractility are multifactorial, but appear to predominantly relate to three fundamental processes: (1) altered muscle membrane excitability, (2) excitation-contraction uncoupling, and (3) altered muscle bioenergetics (Fig. 1). It must be emphasized, however, that most research in these areas has been conducted in animal models of critical illness myopathy (CIM) and sepsis, and is supported by limited evidence from humans.Abnormalities of muscle membrane excitability including decreased conduction velocity, increased relative refractory period, and reduced fiber excitability occur in the cri...

Feeding mitochondria: Potential role of nutritional components to improve critical illness convalescence

“…Bio-energetic failure of skeletal muscle is suggested to be associated with ICU-acquired weakness [14]. The OXPHOS system, essential for ATP production, has been shown to be affected in muscles of critically ill patients [15,19e22] (summarized in Table 1).…”

“…NADH and FADH2 are used as electron donors by the first and second complex. Mitochondria depend on the availability of reduced nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2), which are generated during the utilization of glucose, fatty acids and, to a lesser extent, amino acids [14]. The energy released during the electron transfer through the electron transport chain is used to pump protons (Hþ) in the mitochondrial matrix over the inner mitochondrial membrane into the intermembrane space.…”

“…This process generates a proton gradient across this membrane. The energy stored in this proton gradient is used by THE FOF1-ATPase (complex V), which together with the electron transport chain forms the OXPHOS system, to generate ATP from ADP and inorganic phosphate [14].…”

“…Recently, the attention has shifted towards persistent mitochondrial dysfunction as a critical factor [14], since the majority of patients show a reduced ability to produce ATP, which is called bioenergetic failure [15] (Fig. 1).…”

Hindsight and moving the needle forwards on rehabilitation trial design

“…Our current knowledge directs us towards commencing rehabilitation early following medical stabilisation. However, determining the optimum timepoint requires additional understanding of the underlying biological effects of intensive care unit-acquired weakness including mitochondrial dysfunction, excitation–contraction uncoupling and muscle membrane excitability,14 the optimum nutritional regimen15 and how to distinguish true fatigue from psychological factors influencing patient motivation to participate.…”