A subgroup of patients infected with SARS-CoV-2 remain symptomatic over three months after infection. A distinctive symptom of patients with long COVID is post-exertional malaise, which is associated ...with a worsening of fatigue- and pain-related symptoms after acute mental or physical exercise, but its underlying pathophysiology is unclear. With this longitudinal case-control study (NCT05225688), we provide new insights into the pathophysiology of post-exertional malaise in patients with long COVID. We show that skeletal muscle structure is associated with a lower exercise capacity in patients, and local and systemic metabolic disturbances, severe exercise-induced myopathy and tissue infiltration of amyloid-containing deposits in skeletal muscles of patients with long COVID worsen after induction of post-exertional malaise. This study highlights novel pathways that help to understand the pathophysiology of post-exertional malaise in patients suffering from long COVID and other post-infectious diseases.
Abstract
The ability to efficiently adapt metabolism by substrate sensing, trafficking, storage, and utilization, dependent on availability and requirement, is known as metabolic flexibility. In this ...review, we discuss the breadth and depth of metabolic flexibility and its impact on health and disease. Metabolic flexibility is essential to maintain energy homeostasis in times of either caloric excess or caloric restriction, and in times of either low or high energy demand, such as during exercise. The liver, adipose tissue, and muscle govern systemic metabolic flexibility and manage nutrient sensing, uptake, transport, storage, and expenditure by communication via endocrine cues. At a molecular level, metabolic flexibility relies on the configuration of metabolic pathways, which are regulated by key metabolic enzymes and transcription factors, many of which interact closely with the mitochondria. Disrupted metabolic flexibility, or metabolic inflexibility, however, is associated with many pathological conditions including metabolic syndrome, type 2 diabetes mellitus, and cancer. Multiple factors such as dietary composition and feeding frequency, exercise training, and use of pharmacological compounds, influence metabolic flexibility and will be discussed here. Last, we outline important advances in metabolic flexibility research and discuss medical horizons and translational aspects.
Authors review the ways in which metabolic flexibility influences health and disease. The role of major metabolic organs, endocrine signals, key molecular pathways, and their players are discussed.
Cigarette smoking has a negative effect on respiratory and skeletal muscle function and is a risk factor for various chronic diseases. To assess the effects of 14 days of smoking cessation on ...respiratory and skeletal muscle function, markers of inflammation and oxidative stress in humans. Spirometry, skeletal muscle function, circulating carboxyhaemoglobin levels, advanced glycation end products (AGEs), markers of oxidative stress and serum cytokines were measured in 38 non-smokers, and in 48 cigarette smokers at baseline and after 14 days of smoking cessation. Peak expiratory flow (p = 0.004) and forced expiratory volume in 1 s/forced vital capacity (p = 0.037) were lower in smokers compared to non-smokers but did not change significantly after smoking cessation. Smoking cessation increased skeletal muscle fatigue resistance (p < 0.001). Haemoglobin content, haematocrit, carboxyhaemoglobin, total AGEs, malondialdehyde, TNF-α, IL-2, IL-4, IL-6 and IL-10 (p < 0.05) levels were higher, and total antioxidant status (TAS), IL-12p70 and eosinophil numbers were lower (p < 0.05) in smokers. IL-4, IL-6, IL-10 and IL-12p70 had returned towards levels seen in non-smokers after 14 days smoking cessation (p < 0.05), and IL-2 and TNF-α showed a similar pattern but had not yet fully returned to levels seen in non-smokers. Haemoglobin, haematocrit, eosinophil count, AGEs, MDA and TAS did not significantly change with smoking cessation. Two weeks of smoking cessation was accompanied with an improved muscle fatigue resistance and a reduction in low-grade systemic inflammation in smokers.
Mitochondrial fatty acid oxidation is an essential pathway for energy production, especially during prolonged fasting and sub-maximal exercise. Long-chain fatty acids are the most abundant fatty ...acids in the human diet and in body stores, and more than 15 enzymes are involved in long-chain fatty acid oxidation. Pathogenic mutations in genes encoding these enzymes result in a long-chain fatty acid oxidation disorder in which the energy homeostasis is compromised and long-chain acylcarnitines accumulate. Symptoms arise or exacerbate during catabolic situations, such as fasting, illness and (endurance) exercise. The clinical spectrum is very heterogeneous, ranging from hypoketotic hypoglycemia, liver dysfunction, rhabdomyolysis, cardiomyopathy and early demise. With the introduction of several of the long-chain fatty acid oxidation disorders (lcFAOD) in newborn screening panels, also asymptomatic individuals with a lcFAOD are identified. However, despite early diagnosis and dietary therapy, a significant number of patients still develop symptoms emphasizing the need for individualized treatment strategies. This review aims to function as a comprehensive reference for clinical and laboratory findings for clinicians who are confronted with pediatric and adult patients with a possible diagnosis of a lcFAOD.
Aims/hypothesis
Empagliflozin (EMPA), an inhibitor of the renal sodium–glucose cotransporter (SGLT) 2, reduces the risk of cardiovascular death in patients with type 2 diabetes. The underlying ...mechanism of this effect is unknown. Elevated cardiac cytoplasmic Na
+
(Na
+
c
) and Ca
2+
(Ca
2+
c
) concentrations and decreased mitochondrial Ca
2+
concentration (Ca
2+
m
) are drivers of heart failure and cardiac death. We therefore hypothesised that EMPA would directly modify Na
+
c
, Ca
2+
c
and Ca
2+
m
in cardiomyocytes.
Methods
Na
+
c,
Ca
2+
c
, Ca
2+
m
and Na
+
/H
+
exchanger (NHE) activity were measured fluorometrically in isolated ventricular myocytes from rabbits and rats.
Results
An increase in extracellular glucose, from 5.5 mmol/l to 11 mmol/l, resulted in increased Na
+
c
and Ca
2+
c
levels. EMPA treatment directly inhibited NHE flux, caused a reduction in Na
+
c
and Ca
2+
c
and increased Ca
2+
m
. After pretreatment with the NHE inhibitor, Cariporide, these effects of EMPA were strongly reduced. EMPA also affected Na
+
c
and NHE flux in the absence of extracellular glucose.
Conclusions/interpretation
The glucose lowering kidney-targeted agent, EMPA, demonstrates direct cardiac effects by lowering myocardial Na
+
c
and Ca
2+
c
and enhancing Ca
2+
m
, through impairment of myocardial NHE flux, independent of SGLT2 activity.
Skeletal muscle‐related symptoms are common in both acute coronavirus disease (Covid)‐19 and post‐acute sequelae of Covid‐19 (PASC). In this narrative review, we discuss cellular and molecular ...pathways that are affected and consider these in regard to skeletal muscle involvement in other conditions, such as acute respiratory distress syndrome, critical illness myopathy, and post‐viral fatigue syndrome. Patients with severe Covid‐19 and PASC suffer from skeletal muscle weakness and exercise intolerance. Histological sections present muscle fibre atrophy, metabolic alterations, and immune cell infiltration. Contributing factors to weakness and fatigue in patients with severe Covid‐19 include systemic inflammation, disuse, hypoxaemia, and malnutrition. These factors also contribute to post‐intensive care unit (ICU) syndrome and ICU‐acquired weakness and likely explain a substantial part of Covid‐19‐acquired weakness. The skeletal muscle weakness and exercise intolerance associated with PASC are more obscure. Direct severe acute respiratory syndrome coronavirus (SARS‐CoV)‐2 viral infiltration into skeletal muscle or an aberrant immune system likely contribute. Similarities between skeletal muscle alterations in PASC and chronic fatigue syndrome deserve further study. Both SARS‐CoV‐2‐specific factors and generic consequences of acute disease likely underlie the observed skeletal muscle alterations in both acute Covid‐19 and PASC.
Obesity‐induced insulin resistance and type 2 diabetes mellitus can ultimately result in various complications, including diabetic cardiomyopathy. In this case, cardiac dysfunction is characterized ...by metabolic disturbances such as impaired glucose oxidation and an increased reliance on fatty acid (FA) oxidation. Mitochondrial dysfunction has often been associated with the altered metabolic function in the diabetic heart, and may result from FA‐induced lipotoxicity and uncoupling of oxidative phosphorylation. In this review, we address the metabolic changes in the diabetic heart, focusing on the loss of metabolic flexibility and cardiac mitochondrial function. We consider the alterations observed in mitochondrial substrate utilization, bioenergetics and dynamics, and highlight new areas of research which may improve our understanding of the cause and effect of cardiac mitochondrial dysfunction in diabetes. Finally, we explore how lifestyle (nutrition and exercise) and pharmacological interventions can prevent and treat metabolic and mitochondrial dysfunction in diabetes.
The observation that prior heavy or severe-intensity exercise speeds overall oxygen uptake (
V
˙
O
2
) kinetics, termed the “priming effect”, has garnered significant research attention and its ...underpinning mechanisms have been hotly debated. In the first part of this review, the evidence for and against (1) lactic acidosis, (2) increased muscle temperature, (3) O
2
delivery, (4) altered motor unit recruitment patterns and (5) enhanced intracellular O
2
utilisation in underpinning the priming effect is discussed. Lactic acidosis and increased muscle temperature are most likely not key determinants of the priming effect. Whilst priming increases muscle O
2
delivery, many studies have demonstrated that an increased muscle O
2
delivery is not a prerequisite for the priming effect. Motor unit recruitment patterns are altered by prior exercise, and these alterations are consistent with some of the observed changes in
V
˙
O
2
kinetics in humans. Enhancements in intracellular O
2
utilisation likely play a central role in mediating the priming effect, probably related to elevated mitochondrial calcium levels and parallel activation of mitochondrial enzymes at the onset of the second bout. In the latter portion of the review, the implications of priming on the parameters of the power–duration relationship are discussed. The effect of priming on subsequent endurance performance depends critically upon which phases of the
V
˙
O
2
response are altered. A reduced
V
˙
O
2
slow component or increased fundamental phase amplitude tend to increase the work performable above critical power (i.e. W´), whereas a reduction in the fundamental phase time constant following priming results in an increased critical power.
Background
Many sports require maximal strength and endurance performance. Concurrent strength and endurance training can lead to suboptimal training adaptations. However, how adaptations differ ...between males and females is currently unknown. Additionally, current training status may affect training adaptations.
Objective
We aimed to assess sex-specific differences in adaptations in strength, power, muscle hypertrophy, and maximal oxygen consumption (
V
˙
O
2max
) to concurrent strength and endurance training in healthy adults. Second, we investigated how training adaptations are influenced by strength and endurance training status.
Methods
A systematic review and meta-analysis was conducted according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, and a Cochrane risk of bias was evaluated. ISI Web of science, PubMed/MEDLINE, and SPORTDiscus databases were searched using the following inclusion criteria: healthy adults aged 18–50 years, intervention period of ≥ 4 weeks, and outcome measures were defined as upper- and lower-body strength, power, hypertrophy, and/or
V
˙
O
2max
. A meta-analysis was performed using a random-effects model and reported in standardized mean differences.
Results
In total, 59 studies with 1346 participants were included. Concurrent training showed blunted lower-body strength adaptations in males, but not in females (male: − 0.43, 95% confidence interval − 0.64 to − 0.22, female: 0.08 − 0.34 to 0.49, group difference:
P
= 0.03). No sex differences were observed for changes in upper-body strength (
P
= 0.67), power (
P
= 0.37), or
V
˙
O
2max
(
P
= 0.13). Data on muscle hypertrophy were insufficient to draw any conclusions. For training status, untrained but not trained or highly trained endurance athletes displayed lower
V
˙
O
2max
gains with concurrent training (
P
= 0.04). For other outcomes, no differences were found between untrained and trained individuals, both for strength and endurance training status.
Conclusions
Concurrent training results in small interference for lower-body strength adaptations in males, but not in females. Untrained, but not trained or highly trained endurance athletes demonstrated impaired improvements in
V
˙
O
2max
following concurrent training. More studies on females and highly strength-trained and endurance-trained athletes are warranted.
Clinical Trial Registration
PROSPERO: CRD42022370894.
Key points
Calcium ions regulate mitochondrial ATP production and contractile activity and thus play a pivotal role in matching energy supply and demand in cardiac muscle.
The magnitude and kinetics ...of the changes in free mitochondrial calcium concentration in cardiac myocytes are largely unknown.
Rapid stimulation frequency‐dependent increases but relatively slow decreases in free mitochondrial calcium concentration were observed in rat cardiac myocytes. This asymmetry caused a rise in the mitochondrial calcium concentration with stimulation frequency.
These results provide insight into the mechanisms of mitochondrial calcium uptake and release that are important in healthy and diseased myocardium.
Calcium ions regulate mitochondrial ATP production and contractile activity and thus play a pivotal role in matching energy supply and demand in cardiac muscle. Little is known about the magnitude and kinetics of the changes in free mitochondrial calcium concentration in cardiomyocytes. Using adenoviral infection, a ratiometric mitochondrially targeted Förster resonance energy transfer (FRET)‐based calcium indicator (4mtD3cpv, MitoCam) was expressed in cultured adult rat cardiomyocytes and the free mitochondrial calcium concentration (Ca2+m) was measured at different stimulation frequencies (0.1–4 Hz) and external calcium concentrations (1.8–3.6 mm) at 37°C. Cytosolic calcium concentrations were assessed under the same experimental conditions in separate experiments using Fura‐4AM. The increases in Ca2+m during electrical stimulation at 0.1 Hz were rapid (rise time = 49 ± 2 ms), while the decreases in Ca2+m occurred more slowly (decay half time = 1.17 ± 0.07 s). Model calculations confirmed that this asymmetry caused the rise in Ca2+m during diastole observed at elevated stimulation frequencies. Inhibition of the mitochondrial sodium–calcium exchanger (mNCE) resulted in a rise in Ca2+m at baseline and, paradoxically, in an acceleration of Ca2+ release. In conclusion: rapid increases in Ca2+m allow for fast adjustment of mitochondrial ATP production to increases in myocardial demand on a beat‐to‐beat basis and mitochondrial calcium release depends on mNCE activity and mitochondrial calcium buffering.
Key points
Calcium ions regulate mitochondrial ATP production and contractile activity and thus play a pivotal role in matching energy supply and demand in cardiac muscle.
The magnitude and kinetics of the changes in free mitochondrial calcium concentration in cardiac myocytes are largely unknown.
Rapid stimulation frequency‐dependent increases but relatively slow decreases in free mitochondrial calcium concentration were observed in rat cardiac myocytes. This asymmetry caused a rise in the mitochondrial calcium concentration with stimulation frequency.
These results provide insight into the mechanisms of mitochondrial calcium uptake and release that are important in healthy and diseased myocardium.
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