Tim Constantin

University of Nottingham Medical School · School of Life Sciences

Bed rest (BR) of only a few days duration reduces muscle protein synthesis and induces skeletal muscle atrophy and insulin resistance, but the scale and juxtaposition of these events has not been investigated concurrently in the same individuals. Moreover, the impact of short-term exercise-supplemented remobilisation (ESR) on muscle volume, protein...

Insulin resistance is a risk factor for type 2 diabetes, and exercise can improve insulin sensitivity. However, following exercise, high circulating fatty acid (FA) levels might counteract this. We hypothesized that such inhibition would be reduced by forcibly increasing carbohydrate oxidation through pharmacological activation of the pyruvate dehy...

Background Bed‐rest (BR) of only a few days duration reduces muscle protein synthesis and induces skeletal muscle atrophy and insulin resistance, but the scale and juxtaposition of these events have not been investigated concurrently in the same individuals. Moreover, the impact of short‐term exercise‐supplemented remobilization (ESR) on muscle vol...

A recent study led by FB Stephens (Wall et al., 2023) concluded that caffeine stimulates human muscle carnitine retention during conditions of supraphysiological plasma carnitine concentrations. Although the authors did not provide any other evidence of carnitine data except that in plasma, they anticipated that carnitine with caffeine may represen...

Introduction Diclofenac is an NSAID commonly used off-label to reputedly enhance athletic training adaptation. Diclofenac activates PPAR-γ and upregulates the expression of lipid metabolism genes in vitro. This study investigated the impact of diclofenac administration on IMCL content and muscle genes regulating lipid metabolism during resistance e...

Background Bed rest (BR) reduces whole‐body insulin‐stimulated glucose disposal (GD) and alters muscle fuel metabolism, but little is known about metabolic adaptation from acute to chronic BR nor the mechanisms involved, particularly when volunteers are maintained in energy balance. Methods Healthy males (n = 10, 24.0 ± 1.3 years), maintained in e...

Introduction Inflammation induces changes in muscle protein turnover and mass and dampens insulin stimulated glucose disposal and oxidation. Limited information is available regarding the molecular regulation of these events. We determined the acute effects of lipopolysaccharide (LPS) infusion on targeted muscle mRNA expression. Methods Seven heal...

Introduction Bed-rest (BR) reduces whole-body insulin-stimulated glucose disposal (GD) and alters muscle fuel metabolism. However, little is known about metabolic adaptation from acute to chronic BR, particularly when volunteers are maintained in energy balance. Methods Healthy males (n=10, 24±1.25 years) maintained in energy balance underwent 3 d...

The increasing prevalence of joint disease, and in particular osteoarthritis (OA), calls for novel treatment strategies to prevent disease progression in addition to existing approaches focusing mainly on the relief of pain symptoms. The inherent properties of mesenchymal stem cells (MSCs) make them an attractive candidate for novel tissue repair s...

A recent study by Jameson et al, overseen by Francis Stephens (1), concluded that muscle function recovery from a bout of muscle-damaging one-leg exercise would be faster with a commercial protein drink, “through attenuating the inflammatory [nuclear factor]-kB signaling pathway,” when compared with a sugary drink (control). The nonexercised legs s...

Muscle fatigue (MF) declines the capacity of muscles to complete a task over time at a constant load. MF is usually short-lasting, reversible, and is experienced as a feeling of tiredness or lack of energy. The leading causes of short-lasting fatigue are related to overtraining, undertraining/deconditioning, or physical injury. Conversely, MF can b...

The molecular mechanisms by which free fatty acids (FFA) inhibit muscle glucose oxidation is still elusive. We recently showed that C2C12 myotubes treated with palmitate (PAL) presented with greater protein expression levels of PDK4 and transcription factors PPARα and PPARδ and lower p-FOXO/t-FOXO protein ratios when compared to control. This was c...

COPD patients exhibit lower peak oxygen consumption (V̇O 2 PEAK ), altered muscle metabolism and impaired exercise tolerance compared with age-matched controls. Whether these traits reflect muscle level deconditioning (impacted by ventilatory constraints) and/or dysfunction in mitochondrial ATP production capacity is debated. By studying aerobic ex...

The peroxisome proliferator-activated receptor (PPAR) family of transcription factors has been demonstrated to play critical roles in regulating fuel selection, energy expenditure and inflammation in skeletal muscle and other tissues. Activation of PPARs, through endogenous fatty acids and fatty acid metabolites or synthetic compounds, has been dem...

Carbohydrate metabolism in heart failure shares similarities to that following hypoxic exposure, and is thought to maintain energy homeostasis in the face of reduced O2 availability. As part of these in vivo adaptations during sustained hypoxia, the heart upregulates and maintains a high glycolytic flux, but the underlying mechanism it is still elu...

Background Neuroinflammation is a critical feature of sensitisation of spinal nociceptive processing in chronic pain states. We hypothesised that the resolvin pathways, a unique endogenous control system, may ameliorate aberrant spinal processing of somatosensory inputs associated with chemotherapy-induced neuropathic pain (CINP). Method The pacli...

High‐load eccentric training reputedly produces greater muscle hypertrophy than concentric training, possibly due to greater loading and/or inflammation. We quantified the temporal impact of combined maximal concentric‐eccentric training vs maximal concentric training on muscle cross‐sectional area (CSA), volume and targeted mRNA expression (93 tra...

The mechanisms behind the reduction in muscle pyruvate dehydrogenase complex (PDC)-controlled carbohydrate (CHO) oxidation during chronic high-fat dietary intake are poorly understood, as is the basis of CHO oxidation restoration during muscle contraction. C2C12 myotubes were treated with (300 µM) palmitate or without (control) for 16 h in the pres...

Rheumatoid arthritis (RA) is accompanied by pain, inflammation and muscle weakness. Skeletal muscle inflammation and inactivity are independently associated with muscle insulin resistance and atrophy. Our objective was to identify early molecular and biochemical markers in muscle from a rodent model of RA relative to control and subsequently identi...

Rheumatoid arthritis (RA) is accompanied by pain, inflammation and muscle weakness. Skeletal muscle inflammation and inactivity are independently associated with muscle insulin resistance and atrophy. Our objective was to identify early molecular and biochemical markers in muscle from a rodent model of RA relative to control and subsequently identi...

Background and aims This post hoc study aimed to determine whether major elective abdominal surgery had any acute impact on mitochondrial pyruvate dehydrogenase complex (PDC) activity and maximal mitochondrial ATP production rates (MAPR) in a large muscle group (vastus lateralis -VL) distant to the site of surgical trauma. Methods Fifteen patients...

Objective: Myokines, such as Irisin, have been purported to exert physiological effects on skeletal muscle in an autocrine/paracrine fashion. In this study, we aimed to investigate the mechanistic role of in vivo Fndc5/Irisin upregulation in muscle. Methods: Overexpression (OE) of Fndc5 in rat hind-limb muscle was achieved by in vivo electro-tra...

Increased risk of type 2 diabetes mellitus (T2DM) is linked to impaired muscle mitochondrial function and reduced mitochondrial DNA copy number (mtDNAnum). However, studies have failed to control for habitual physical activity levels, which directly influences both mtDNA copy number and insulin sensitivity. We, therefore, examined whether physical...

Glioblastoma therapeutic challenges are in considerable part due to myriad survival mechanisms which allow malignant cells to repurpose signalling pathways within discreet microenvironments. These Darwinian adaptations facilitate invasion into brain parenchyma and perivascular space. We hypothesised that pre-clinical modelling of glioma invasion by...

Glioblastoma therapeutic challenges are in considerable part due to myriad survival adaptations and mechanisms, which allow malignant cells to repurpose signalling pathways within discreet microenvironments. These Darwinian adaptations facilitate invasion into brain parenchyma and perivascular space or promote evasion from repressive factors that r...

Background: Inorganic nitrate, abundant in leafy green vegetables and beetroot, is thought to have protective health benefits. Adherence to a Mediterranean diet reduces the incidence and severity of coronary artery disease, whereas supplementation with nitrate can improve submaximal exercise performance. Once ingested, oral commensal bacteria may...

Background: The andropause is associated with declines in serum testosterone (T), loss of muscle mass (sarcopenia), and frailty. Two major interventions purported to offset sarcopenia are anabolic steroid therapies and resistance exercise training (RET). Nonetheless, the efficacy and physiological and molecular impacts of T therapy adjuvant to sho...

The expression of human endogenous retroviruses (HERVs) has been associated with Multiple Sclerosis (MS). The MS-related retrovirus (MSRV/HERV-W) has the potential to activate inflammatory immunity, which could promote both susceptibility and progression toward MS. A connection between HERVs and MS is also supported by the observation that people i...

Sarcopenia, the age-related decline of muscle, is a significant and growing public health burden. C. elegans, a model organism for investigating the mechanisms of ageing, also displays sarcopenia, but the underlying mechanism(s) remain elusive. Here, we use C. elegans natural scaling of lifespan in response to temperature to examine the relationshi...

Loss of muscle mass and insulin sensitivity are common phenotypic traits of immobilisation and increased inflammatory burden. The suppression of muscle protein synthesis is the primary driver of muscle mass loss in human immobilisation, and includes blunting of post‐prandial increases in muscle protein synthesis. However, the mechanistic drivers of...

Balanced vegetarian diets are popular, although they are nearly absent in creatine and carnosine and contain considerably less carnitine than non-vegetarian diets. Few longitudinal intervention studies investigating the effect of a vegetarian diet on the availability of these compounds currently exist. We aimed to investigate the effect of transien...

Background & aims: Exercise activates muscle pyruvate dehydrogenase complex (PDC), but moderate intensity exercise fails to fully activate muscle PDC after high-fat diet [1]. We investigated whether maximal intensity exercise overcomes this inhibition. Methods: Quadriceps femoris muscle biopsy samples were obtained from healthy males at rest, an...

Key points: The cardiac metabolic reprogramming seen in heart diseases such as myocardial infarction and hypertrophy shares similarities with that seen in chronic hypoxia, but understanding of how the hypoxic heart responds to further hypoxic challenge - hypoxic tolerance - is limited. The pyruvate dehydrogenase complex serves to control irreversi...

Background & aims: Postoperative hyperglycaemia is common in patients having major surgery and is associated with adverse outcomes. This study aimed to determine whether bacteraemia contributed to postoperative systemic inflammation, and whether increases in the expression of muscle mRNAs and proteins reflecting increased muscle inflammation, atro...

Key points: Meldonium inhibits endogenous carnitine synthesis and tissue uptake, and accelerates urinary carnitine excretion, although the impact of meldonium-mediated muscle carnitine depletion on whole-body fuel selection, and muscle fuel metabolism and its molecular regulation is under-investigated. Ten days of oral meldonium administration did...

The peroxisome proliferator-activated receptor γ (PPARγ) agonist rosiglitazone (Rosi) appears to provide protection against organ dysfunction during endotoxaemia. We examined the potential benefits of Rosi on skeletal muscle protein maintenance and carbohydrate metabolism during lipopolysaccharide (LPS)-induced endotoxaemia. Sprague-Dawley rats wer...

The ubiquitin–proteasome system (UPS) and macroautophagy (autophagy) are central to normal proteostasis and interdependent in that autophagy is known to compensate for the UPS to alleviate ensuing proteotoxic stress that impairs cell function. UPS and autophagy dysfunctions are believed to have a major role in the pathomechanisms of neurodegenerati...

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Key points: This study aimed to provide molecular insight into the differential effects of age and physical inactivity on the regulation of substrate metabolism during moderate-intensity exercise. Using the arteriovenous balance technique, we studied the effect of immobilization of one leg for 2 weeks on leg substrate utilization in young and olde...

Modulation of cardiac pyruvate dehydrogenase complex (PDC) flux is known to alter post-ischemic myocardial injury. Hypoxia is intrinsic to ischemia, but its specific role in cardiac injury is unknown. We hypothesized that post-hypoxic cardiac injury would be attenuated with activation of the PDC complex during hypoxia. Mouse hearts were isolated an...

Background Declines in skeletal muscle structure and function are found in various clinical populations, but the intramuscular proteolytic pathways that govern declines in these individuals remain relatively poorly understood. The nematode Caenorhabditis elegans has been developed into a model for identifying and understanding these pathways. Recen...

CD4(+)CD25(hi) FOXP3(+) regulatory T cells (Tregs) maintain tolerance to self-Ags. Their defective function is involved in the pathogenesis of multiple sclerosis (MS), an inflammatory demyelinating disease of the CNS. However, the mechanisms of such defective function are poorly understood. Recently, we reported that stimulation of TLR2, which is p...

Rahimi et al. (1) state that “whether fatty acids induce [muscle] insulin resistance by decreasing PDH [pyruvate dehydrogenase complex] flux remains unknown” and “the role of PDH and mitochondrial oxidative substrate selection in the regulation of basal and insulin-stimulated muscle glucose metabolism has not been directly assessed in vivo.” Theref...

Statins are associated with muscle myalgia and myopathy, which probably reduce habitual physical activity. This is particularly relevant to older people who are less active, sarcopaenic and at increased risk of statin myalgia. We hypothesised that statin myalgia would be allied to impaired strength and work capacity in older people, and determined...

We hypothesized that the so far poorly understood improvement in postoperative insulin sensitivity, when surgery is preceded by a carbohydrate (CHO) drink, occurs via attenuation of skeletal muscle inflammatory responses to surgery, improved insulin signaling and attenuated expression of muscle pyruvate dehydrogenase kinase (PDK) 4. Vastus laterali...

The integrin-adhesome network, which contains >150 proteins, is mechano-transducing and located at discreet positions along the cell-cell and cell-extracellular matrix interface. A small subset of the integrin-adhesome is known to maintain normal muscle morphology. However, the importance of the entire adhesome for muscle structure and function is...

Key points Statins cause muscle‐specific side effects, most commonly muscle aches/weakness (myalgia), particularly in older people. Furthermore, evidence has linked statin use to increased risk of type 2 diabetes. However, the mechanisms involved are unknown. This is the first study to measure muscle protein turnover rates and insulin sensitivity i...

Critically ill patients admitted to hospital often present with selective skeletal muscle loss, which severely compromises muscle function and clinical outcomes such as morbidity, mortality and the length of hospitalisation. We provide here novel and interesting translational data from our and other groups, which show how skeletal muscle mass is re...

Since the mitochondrial pyruvate dehydrogenase complex (PDC) controls the rate of carbohydrate oxidation, impairment of PDC activity mediated by high-fat intake has been advocated as a causative factor for the skeletal muscle insulin resistance, metabolic syndrome, and the onset of type 2 diabetes (T2D). There are also situations where muscle insul...