The impact of severe burns on skeletal muscle mitochondrial function

Abstract

Severe burns induce a pathophysiological response that affects almost every physiological system within the body. Inflammation, hypermetabolism, muscle wasting, and insulin resistance are all hallmarks of the pathophysiological response to severe burns, with perturbations in metabolism known to persist for several years post injury. Skeletal muscle is the principal depot of lean tissue within the body and as the primary site of peripheral glucose disposal, plays an important role in metabolic regulation. Following a large burn, skeletal muscle functions as and endogenous amino acid store, providing substrates for more pressing functions, such as the synthesis of acute phase proteins and the deposition of new skin. Subsequently, burn patients become cachectic, which is associated with poor outcomes in terms of metabolic health and functional capacity. While a loss of skeletal muscle contractile proteins per se will no doubt negatively impact functional capacity, detriments in skeletal muscle quality, i.e. a loss in mitochondrial number and/or function may be quantitatively just as important. The goal of this review article is to summarise the current understanding of the impact of thermal trauma on skeletal muscle mitochondrial content and function, to offer direction for future research concerning skeletal muscle mitochondrial function in patients with severe burns, and to renew interest in the role of these organelles in metabolic dysfunction following severe burns.

Introduction

The pathophysiological response to thermal trauma is multi-factorial with resulting perturbations in metabolism affecting nearly every physiological system [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16]. Like most forms of critical illness, severe burns result in an inflammatory and hypermetabolic stress response, but the extent and duration of these responses and their debilitating nature appear unique to burn trauma [1], [6], [7], [17], [18], [19], [20]. With recent advances in clinical practice such as early wound excision and closure, and robust infection management [21], severe burns are more survivable than ever before. Consequently, there is a real need for effective rehabilitative strategies that mitigate the pathophysiological response to burns and to restore normal physiological function in order to reduce morbidity and improve quality of life in patients recovering from severe burns. Central to the process of developing novel strategies that impact outcomes in burn patients is a comprehensive understanding of the pathophysiological response to severe burn trauma. While the stress response to burn trauma including but not limited to inflammation, the catecholamine surge, hypermetabolism and muscle wasting have been studied in human patients in great detail [1], [5], [6], [9], [10], [17], [19], [20], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], the impact of severe burns on skeletal muscle bioenergetics in human patients has been paid comparatively little attention [42], [43], [44], [45], [46]. This is perhaps surprising given the fact that supraphysiological rates of energy expenditure [1], [5], [18], [19], [23], [33], [47], [48], [49], insulin resistance [1], [4], [5], [29], [45], [50], [51] and muscle wasting [6], [14], [17], [19], [23], [25], [26], [28], [30], [31], [32], [34], [35], [36], [37], [38], [39], [40] are all considered as hallmarks of the pathophysiological response to severe burns. Moreover, mitochondria are sensitive to environmental and pharmacological stimuli [52], [53], [54], [55], meaning that these intriguing organelles make ideal candidates for interventions aimed at altering the pathophysiology of burn trauma. With this in mind, the purpose of this article is to review the current literature pertaining to skeletal muscle bioenergetics in patients with severe burns, with an aim to renewing interest in this field and wherever possible, offer direction to researchers interested in improving metabolic health and functional capacity in patients recovering from severe burns.