Metabolic phenotype of skeletal muscle in early critical illness

Puthucheary, Zudin; Astin, Rónan; McPhail, Mark; Saeed, Saima; Pasha, Y A Zahed; Bear, Danielle E.; Constantin, Despina; Velloso, Cristiana P.; Manning, Sean; Calvert, L.D.; Singer, Mervyn; Batterham, Rachel L.; Gómez-Romero, María José; Holmes, Elaine; Steiner, Michael; Atherton, Philip J.; Greenhaff, Paul L.; Edwards, Lindsay M.; Smith, Kenneth; Harridge, Stephen; Hart, Nicholas; Montgomery, Hugh

doi:10.1136/thoraxjnl-2017-211073

Cited by 142 publications

(178 citation statements)

References 56 publications

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“…[47][48][49][50] Mitochondrial myopathy has been suggested to play an important role in the skeletal muscle dysfunction, and poor physical functioning common in patients with CKD. ***Denotes P < .001 vs healthy controls.…”

Section: Discussionmentioning

confidence: 99%

Reductions in skeletal muscle mitochondrial mass are not restored following exercise training in patients with chronic kidney disease

et al. 2019

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Patients with chronic kidney disease (CKD) exhibit reduced exercise capacity, poor physical function and symptoms of fatigue. The mechanisms that contribute to this are not clearly defined but may involve reductions in mitochondrial function, mass and biogenesis. Here we report on the effect of non-dialysis dependent CKD (NDD-CKD) on mitochondrial mass and basal expression of transcription factors involved in mitochondrial biogenesis compared to a healthy control cohort (HC). In addition, we sought to investigate the effect of a 12-week exercise-training programme on these aspects of mitochondrial dysfunction in a NDD-CKD cohort.For the comparison between NDD-CKD and HC populations, skeletal muscle biopsies were collected from the vastus lateralis (VL) of n=16 non-dialysis dependent CKD patient's stage 3b-5 (NDD-CKD) and n=16 healthy controls matched for age, gender and physical activity (HC). To investigate the effect of exercise training, VL biopsies were collected from n=17 NDD-CKD patients before and after a 12-week exercise intervention that was comprised of aerobic exercise (AE) or a combination of aerobic exercise and resistance training (CE). Mitochondrial mass was analysed by citrate synthase activity and mitochondrial protein content by Porin expression, whilst the expression of transcription factors involved in mitochondrial biogenesis were quantified by real-time qPCR. NDD-CKD patients exhibited a significant reduction in mitochondrial mass when compared to HC, coupled to a reduction in PGC-1α, NRF-1, Nrf2, TFam, mfn2 and SOD1/2 gene expression. 12-weeks of exercise training resulted in a significant increase in PGC-1α expression in both groups, with no further changes seen across indicators of mitochondrial biogenesis. No significant changes in mitochondrial mass were observed in response to either exercise programme. NDD-CKD patients exhibit reduced skeletal muscle mitochondrial mass and gene expression of 1756 |

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Section: Discussionmentioning

confidence: 99%

Reductions in skeletal muscle mitochondrial mass are not restored following exercise training in patients with chronic kidney disease

et al. 2019

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“…The severity of the acute illness determines the degree of muscle wasting,51 with age, ICU length of stay, systemic inflammation and chronic health prior to critical illness determining the trajectory of recovery 58. In addition, decreased mitochondrial biogenesis and dysregulated lipid oxidation contribute to a compromised skeletal muscle bioenergetic status with intramuscular inflammation associated with impaired anabolic recovery60 and development of ICU-acquired weakness 61. Future clinical work will need to focus on these key areas with the establishment of the appropriate timing, dose and frequency of both pharmacological and non-pharmacological treatments.…”

Section: Early Rehabilitation During Critical Illnessmentioning

confidence: 99%

Pulmonary rehabilitation, physical activity, respiratory failure and palliative respiratory care

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et al. 2019

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“…In the inflammatory setting, pyruvate dehydrogenase, which serves as the key gatekeeper to the Krebs cycle, is inhibited, and carbohydrate metabolism is shunted toward anaerobic pathways, resulting in lactate production . Lipogenesis is inhibited, and mitochondrial β‐oxidation of fat may be impaired, resulting in the inability to utilize fat during this period . As a result, proteolysis (predominately from lean body mass) becomes a primary contributor for ongoing substrate provision.…”

Section: The Hypermetabolic Response In Burn Patientsmentioning

confidence: 99%

“…The time frame by which the assault on skeletal muscle occurs is swift. A 2018 study by Puthucheary et al demonstrated decreased intramuscular ATP 1 day following an inflammatory insult, potentially related to the intentional redirection of substrate to fulfill alternative fuel requirements . Skeletal muscle becomes a source of amino acids both as precursors for gluconeogenesis and later as substrate for the healing of burn wounds .…”

Section: The Hypermetabolic Response In Burn Patientsmentioning

confidence: 99%

“…[36][37][38][39] Lipogenesis is inhibited, and mitochondrial β-oxidation of fat may be impaired, resulting in the inability to utilize fat during this period. 40 As a result, proteolysis (predominately from lean body mass) becomes a primary contributor for ongoing substrate provision. Early work in critically ill trauma patients suggests that both protein synthesis and catabolism are increased but that the increase in proteolysis is far greater than the increase in synthesis, resulting in an overall negative nitrogen balance.…”

Section: The Hypermetabolic Response In Burn Patientsmentioning

confidence: 99%

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Energy Expenditure and Protein Requirements Following Burn Injury

2019

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Severe burn injuries have long been known to have a profound effect on metabolic equilibrium that can persist after resolution of the cutaneous injuries. Following burn injury, metabolism is a dynamic state resulting in the need for frequent interval reassessment over the course of the care continuum. The acute phase of injury transitions to chronic alterations in macronutrient utilization characterized by futile energy cycling and disproportionate catabolism of skeletal muscle. Protein supplementation appears to be preferentially distributed to the burn wound rather than the skeletal muscle pool. Accurate assessment of caloric and protein requirements is extremely difficult in these patients but is an essential step in efforts to attenuate functional impairment. Indirect calorimetry should be utilized to determine caloric requirements, but trophic feeding strategies are preferred in the initial resuscitative phase to prevent overfeeding while maintaining enteric and immune function. Controversy persists regarding optimal protein targets, and weight‐based estimates remain the norm. Exogenous protein and caloric provision performed in isolation is insufficient to optimize outcomes and should be incorporated within a multidisciplinary approach to include muscle loading and pharmaceutical adjuncts.

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Metabolic phenotype of skeletal muscle in early critical illness

Abstract: NCT01106300.

Cited by 142 publications

References 56 publications

Reductions in skeletal muscle mitochondrial mass are not restored following exercise training in patients with chronic kidney disease

Reductions in skeletal muscle mitochondrial mass are not restored following exercise training in patients with chronic kidney disease

Pulmonary rehabilitation, physical activity, respiratory failure and palliative respiratory care

Energy Expenditure and Protein Requirements Following Burn Injury

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