Charles Lang

Penn State Hershey Medical Center and Penn State College of Medicine · Cellular and Molecular Physiology

Introduction: Because of the strong correlation between the blood concentration of circulating resistin and the illness severity of septic patients, resistin has been proposed as a mediator of sepsis pathophysiology. In vitro data indicate that human resistin directly impairs neutrophil migration and intracellular bacterial killing, although the s...

Circadian rhythms are central to optimal physiological function as disruption contributes to the development of several chronic diseases. Alcohol (EtOH) intoxication disrupts circadian rhythms within liver, brain, and intestines, but it is unknown whether alcohol also disrupts components of the core clock in skeletal muscle. Female C57BL/6Hsd mice...

The Ragulator protein complex is critical for directing the Rag GTPase proteins and mTORC1 to the lysosome membrane mediating amino acid-stimulated protein synthesis. As there is a lack of evidence on alcohol’s effect on the Rag-Ragulator complex as a possible mechanism for the development of alcoholic skeletal muscle wasting, the aim of our study...

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monit...

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monit...

the PDF can be download freely on pubmed. https://pubmed.ncbi.nlm.nih.gov/33634751/

We examined the hypothesis that exaggerating unloading‐induced bone loss using a combination of hindlimb suspension (HLS) and exogenous injections of receptor activator of nuclear factor‐κB ligand (RANKL) also exaggerates gastrocnemius and quadriceps muscle loss. Forty, male C57Bl/6J mice (16 weeks) were subjected to HLS or normal ambulation (groun...

Space travel and prolonged bed rest are examples of mechanical unloading that induce significant muscle and bone loss. The compromised structure and function of bone and muscle owing to unloading make the reloading period a high risk for injury. To explore interactions between skeletal bone and muscle during reloading, we hypothesized that acute ex...

We examined the hypothesis that exaggerating unloading-induced bone loss using a combination of hindlimb suspension (HLS) and exogenous injections of receptor activator of nuclear factor kappa-B ligand (RANKL) also exaggerates muscle loss. Forty, male C57Bl/6J mice (16 weeks) were subjected to HLS or normal ambulation (ground control, GC) for 14 da...

Space travel and prolonged bed rest are examples of mechanical unloading that induce significant muscle and bone loss. To explore interactions between skeletal bone and muscle during reloading, we hypothesized that acute external mechanical loading of bone in combination with re-ambulation facilitates proportional recovery of bone and muscle lost d...

Convalescence in humans after severe sepsis occurs over weeks to months and is associated with prolonged functional disabilities and impaired quality-adjusted survival. While much is known regarding the acute early phase of sepsis, there is a knowledge gap pertaining to restoration of muscle mass and function after elimination of the septic nidus....

Background: Sepsis-induced immunosuppression is a key factor contributing to the morbidity and mortality of critically ill patients, and polymorphonuclear neutrophil dysfunction is believed to be a hallmark of this immunosuppression. Circulating myeloid cells produce the cytokine resistin (RETN), which has been associated with poor outcomes in sep...

Background: Skeletal muscle myopathy accompanying chronic alcohol misuse results in part from a decrease in protein synthesis typically observed in type II-rich muscles that leads to muscle weakness. However, there are a paucity of studies investigating whether the alcohol-induced weakness is intrinsic to the muscle or results primarily from the l...

The purpose of this study was to determine the impact of acute ethanol administration on the major signal transduction pathways in skeletal muscle responsible for regulating the protein synthetic and degradative response to refeeding. Adult male C57Bl/6 mice were fasted overnight; mice were then either refed normal rodent chow for 30 min or a separ...

Perinatal high-fat diet (pHFD) exposure increases the inhibition of dorsal motor nucleus of the vagus (DMV) neurons, potentially contributing to the dysregulation of gastric functions. The aim of this study was to test the hypothesis that pHFD increases the inhibition of DMV neurons by disrupting GABAA receptor subunit development. In vivo gastric...

Previous studies indicate women have a higher blood alcohol (i.e., ethanol) and acetaldehyde concentration after consuming an equivalent amount of alcohol, and that women are more susceptible to the long‐term negative health effects of alcohol. However, there is a paucity of data pertaining to whether there is a sexual dimorphic response in skeleta...

Both acute intoxication and longer-term cumulative ingestion of alcohol negatively impact the metabolic phenotype of both skeletal and cardiac muscle, independent of overt protein calorie malnutrition, resulting in loss of skeletal muscle strength and cardiac contractility. In large part, these alcohol-induced changes are mediated by a decrease in...

Ethanol produces a state of anabolic resistance in skeletal muscle; however, whether the heart displays a similar defect is unknown. Hence, the purpose of this study was to determine the impact of acute ethanol administration on the major signal transduction pathways in heart that are responsible for regulating the protein synthetic and degradative...

Astronauts in space experience a unique environment that causes the concomitant loss of bone and muscle. However, the interaction between these tissues and how osteopenia and sarcopenia affect each other is unclear. We explored this relationship by exaggerating unloading-induced muscle loss using a unilateral casting model in conjunction with hindl...

Background: Cardiac dysfunction is a common manifestation of sepsis and is associated with early increases in inflammation and decreases in myocardial protein synthesis. However, little is known regarding the molecular mechanisms regulating protein homeostasis during the recovery phase after the removal of the septic nidus. Therefore, the purpose...

Deep space travel exposes astronauts to extended periods of space radiation and mechanical unloading, both of which may induce significant muscle and bone loss. Astronauts are exposed to space radiation from solar particle events (SPE) and background radiation referred to as galactic cosmic radiation (GCR). To explore interactions between skeletal...

Putative mechanisms leading to the development of alcoholic cardiomyopathy (ACM) include the interrelated cellular processes of mitochondria metabolism, oxidative stress and apoptosis. As mitochondria fuel the constant energy demands of this continually contracting tissue, it is not surprising that alcohol-induced molecular changes in this organell...

Alcoholic cardiomyopathy (ACM) can develop after consumption of relatively large amounts of alcohol over time or from acute binge drinking. Of the many factors implicated in the etiology of ACM, chronic perturbation in protein balance has been strongly implicated. This review focuses on recent contributions (since 2010) in the area of protein metab...

Background: Excessive alcohol (EtOH) consumption causes imbalances in protein metabolism. EtOH impairs protein synthesis in C2C12 myoblasts via a FoxO1-AMPK-TSC2-mTORC1 pathway and also induces degradation. As the underlying regulatory signaling cascades for these processes are currently poorly defined, we tested the hypothesis that alcohol-induce...

Chronic alcohol consumption perturbs lipid metabolism as it increases adipose tissue lipolysis and leads to ectopic fat deposition within the liver and the development of alcoholic fatty liver disease. In addition to the recognition of the role of adipose tissue derived fatty acids in liver steatosis, alcohol also impacts other functions of adipose...

Adipose tissue is an important energy depot and endocrine organ, and the degree of adiposity impacts the host response to infection. However, little is known regarding the mechanisms by which white adipose tissue (WAT) is lost acutely and then restored after resolution of sepsis. Therefore, signaling pathways governing protein synthesis, autophagy,...

Background: Mild dietary zinc (Zn) deficiency is widespread in human populations, but its influence on recovery after acute illness is poorly understood. In a mouse model of abdominal sepsis (cecal ligation puncture), systemic immune responses and liver metabolism were monitored in early (24 h) and late (5 d) phases, under control conditions and d...

Severe zinc deficiency is associated with an increased systemic inflammatory response and mortality after sepsis. However, the impact of mild zinc deficiency, which is more common in populations with chronic illnesses and sepsis, is unknown. In this study, we hypothesized that marginal dietary Zn deprivation (ZM) would amplify tissue inflammation a...

Muscle deconditioning is commonly observed in patients surviving sepsis. Little is known regarding the molecular mechanisms regulating muscle protein homeostasis during the recovery or convalescence phase. We adapted a sepsis-recovery mouse model that uses cecal ligation and puncture (CLP), followed 24 h later by cecal resection and antibiotic trea...

Background: Chronic alcohol consumption leads to a loss of white adipose tissue (WAT) but the underlying mechanisms for this lipodystrophy are not fully elucidated. This study tested the hypothesis that the reduction in WAT mass in chronic alcohol-fed mice is associated with a decreased protein synthesis specifically related to impaired function o...

This review summarizes the American Physiological Society (APS) Presidential Symposium 1 entitled Physiological Processes Underlying Organ Injury in Alcohol Abuse at the 2016 Experimental Biology meeting. The symposium was organized by Dr. Patricia Molina, past president of the APS, was held on April 03 at the Convention Center in San Diego, CA and...

Muscle wasting resulting wholly or in part from disuse represents a serious medical complication, which when prolonged, can increase morbidity and mortality. Although much knowledge has been gained over the past half century, the underlying etiology by which disuse alters muscle proteostasis remains enigmatic. Multidisciplinary and novel methodolog...

On September 27, 2015 the 20th annual Alcohol and Immunology Research Interest Group (AIRIG) meeting was held as a satellite symposium at the annual meeting of the Society for Leukocyte Biology in Raleigh, NC. The 2015 meeting focused broadly on adverse effects of alcohol and alcohol-use disorders in multiple organ systems. Divided into two plenary...

Since its discovery, the protein Regulated in Development and DNA Damage 1 (REDD1) has been implicated in the cellular response to various stressors. Most notably, its role as a repressor of signaling through the central metabolic regulator, the mechanistic target of rapamycin in complex 1 (mTORC1) has gained considerable attention. Not surprisingl...

The mammalian target of rapamycin (mTOR) is a major regulator of protein synthesis, whereas the ubiquitin-proteasome system (UPS) is regarded as the main proteolytic pathway in skeletal muscle. The objective of the current study was to investigate the effects of slow-release urea and rumen-protected (RP) Met and His supplementation of a metabolizab...

Sepsis-induced skeletal muscle atrophy and weakness is due in part to decreased mTORC1-mediated protein synthesis and increased proteolysis via the autophagy-lysosomal system and ubiquitin-proteasome pathway. The REDD (Regulated in development and DNA damage)-1 protein is increased in sepsis and can negatively regulate mTORC1 activity. However, the...

Alcohol has profound effects on tissue and whole-body fuel metabolism which contribute to the increased morbidity and mortality in individuals with alcohol use disorder. This review focuses on the glucose metabolic effects of alcohol, primarily in the muscle, liver and adipose tissue, under basal postabsorptive conditions and in response to insulin...

Aims: To determine the causative role of the REDD (regulated in development and DNA damage)-1 protein, a known negative regulator of mTOR kinase, in changes in muscle protein synthesis induced by acute alcohol administration. Methods: Adult female REDD1(-/-) or wild-type (WT) mice were injected IP with ethanol (alcohol; 3 g/kg BW) or saline and...

The production of fibrosis in response to chronic alcohol abuse is well recognized in liver but has not been fully characterized in striated muscle and may contribute to functional impairment. Therefore, the purpose of this study was to use an unbiased discovery-based approach to determine the effect of chronic alcohol consumption on the expression...

Septic shock, the most severe complication associated with sepsis, is manifested by tissue hypoperfusion due, in part, to cardiovascular and autonomic dysfunction. In many cases, the splanchnic circulation becomes vasoplegic. The celiac-superior mesenteric ganglion (CSMG) sympathetic neurons provide the main autonomic input to these vessels. We use...

Alcohol abuse, either by acute intoxication or prolonged excessive consumption, leads to pathological changes in many organs and tissues including skeletal muscle. As muscle protein serves not only a contractile function, but also as a metabolic reserve for amino acids which are used to support the energy needs of other tissues, its content is tigh...

Chronic alcohol consumption leads to muscle weakness and atrophy in part by suppressing protein synthesis and mTORC1-mediated signaling. However, it is unknown whether moderate alcohol consumption also prevents overload-induced muscle growth and related anabolic signaling. Hypertrophy of the plantaris muscle was induced by removal of a section of t...

In skeletal muscle, the nutrient-induced stimulation of protein synthesis requires signaling through the mechanistic target of rapamycin complex 1 (mTORC1). Expression of the repressor of mTORC1 signaling, regulated in development and DNA damage 1 (REDD1), is elevated in muscle during various atrophic conditions and diminished under hypertrophic co...

Background Alcohol (ethanol [EtOH]) intoxication antagonizes stimulation of muscle protein synthesis and mammalian target of rapamycin (mTOR) signaling. However, whether the anabolic response can be reversed when alcohol is consumed after the stimulus is unknown.MethodsA single bout of electrically stimulated muscle contractions (10 sets of 6 contr...

A variety of stressors including alcohol (EtOH) are known to induce collagen production and fibrotic diseases. Matrix metalloproteinases (MMP) play an important role in regulating fibrosis, but little is known regarding the relationship between EtOH and MMPs. In addition, the signaling cascades involved in this process have not been elucidated. We...

Electrically stimulated muscle contraction is a potential clinical therapy to treat sepsis-induced myopathy; however, whether sepsis alters contraction-induced anabolic signaling is unknown. Polymicrobial peritonitis was produced by cecal ligation and puncture (CLP) in male C57BL/6 mice and time-matched, pair-fed controls (CON). At ~24 h post-CLP,...

Alcohol (EtOH) decreases protein synthesis, mTOR-mediated signaling and blunts the anabolic response to growth factors in skeletal muscle. The purpose of the current investigation was to determine whether acute alcohol intoxication antagonizes the contraction-induced increase in protein synthesis and mTOR signaling in skeletal muscle. Fasted male m...

The present study tested the hypothesis that sepsis-induced leucine (Leu) resistance in skeletal muscle is associated with a down-regulation of amino acid transporters important in regulating Leu flux or an impairment in the formation of the Leu-sensitive mTOR-Ragulator complex. Sepsis in adult male rats decreased basal protein synthesis in gastroc...

Insulin acts within the central nervous system to regulate food intake and sympathetic nerve activity (SNA). Strong evidence indicates that glucocorticoids impair insulin-mediated glucose uptake and food intake. However, few data are available regarding whether glucocorticoids also modulate the sympathoexcitatory response to insulin. Therefore, the...

Regulated in DNA Damage and Development 1 (REDD1) is a repressor of mTORC1 signaling. In humans, REDD1 mRNA expression in skeletal muscle is repressed following resistance exercise in association with activation of mTORC1. However, whether REDD1 protein expression is also reduced after exercise and if so to what extent the loss contributes to exerc...

Skeletal muscle, the largest organ in vertebrates, plays a major role in homeostasis. The ubiquitin-proteasome system (UPS) is regarded as the main proteolytic pathway in muscle. It requires the coordinated reactions of 3 enzymes including ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin ligases (E3). We hypothesiz...

The mammalian target of rapamycin (mTOR) signaling pathway is mediated by two functionally distinct multi-protein complexes, mTORC1 and mTORC2. The mTORC1 is a nutrient sensor, in particular of amino acids, activating protein synthesis by phosphorylation of ribosomal protein S6 kinase (S6K1) and eukaryotic initiation factor 4E-binding protein (4E-B...

Sepsis decreases skeletal muscle protein synthesis in part by impairing mTOR activity and the subsequent phosphorylation of 4E-BP1 and S6K1 thereby controlling translation initiation; however, the relative importance of changes in these two downstream substrates is unknown. The role of 4E-BP1 (and -BP2) in regulating muscle protein synthesis was as...

Chronic alcoholism impairs pulmonary immune homeostasis and predisposes to inflammatory lung diseases, including infectious pneumonia and acute respiratory distress syndrome. While alcoholism has been shown to alter hepatic metabolism leading to lipid accumulation, hepatitis, and eventually cirrhosis, the effects of alcohol on pulmonary metabolism...

Mechanical unloading induces muscle atrophy and bone loss; however, the time course and interdependence of these effects is not well defined. We subjected 4-month-old C57BL/6J mice to hindlimb suspension (HLS) for three weeks, sacrificing 12-16 mice on day (D) 0, 7, 14, and 21. Lean mass was 7-9% lower for HLS vs. control from D7-21. Absolute mass...

Many preclinical studies in critical care medicine and related disciplines rely on hypothesis-driven research in mice. The underlying premise posits that mice sufficiently emulate numerous pathophysiological alterations produced by trauma/sepsis and can serve as an experimental platform for answering clinically relevant questions. Recently the lay...

Chronic ethanol (EtOH) consumption impairs the ability of insulin to suppress hepatic glucose production in a strain-dependent manner, with hepatic insulin resistance being greater in Long-Evans (LE) than Sprague-Dawley (SD) rats. We assessed whether strain differences exist for whole-body and tissue glucose uptake under basal and insulin-stimulate...

Small molecule nonpeptidyl molecules are potentially attractive drug candidates as adjunct therapies in the treatment of sepsis-induced metabolic complications. As such, the current study investigates the use of aurintricarboxylic acid (ATA), which stimulates insulin-like growth factor (IGF)-I receptor and AKT signaling, for its ability to ameliora...

The purpose of this study was to assess whether the deleterious effect of chronic alcohol consumption differs in adult and aged female rats. To address this aim, adult (4 m) and aged (18 m) F344 rats were fed a nutritionally complete liquid diet containing alcohol (36% total calories) or an isocaloric isonitrogenous control diet for 20 wks. Cardiac...

Ethanol (EtOH) decreases muscle protein synthesis, and this is associated with reduced mammalian target of rapamycin complex (mTORC)1 and increased mTORC2 activities. In contrast, phospholipase D (PLD) and its metabolite phosphatidic acid (PA) positively regulate mTORC1 signaling, whereas their role in mTORC2 function is less well defined. Herein,...

Muscle disuse atrophy is routinely observed in patients recovering from traumatic injury and can be either generalized resulting from extended bed rest or localized resulting from single limb immobilization. The present study addressed the hypothesis that a diet containing 5% alpha-hydroxyisocaproic acid (αHICA), a leucine (Leu) metabolite, will sl...

Focal adhesion kinase (FAK) is an attachment complex protein associated with the regulation of muscle mass, through as of yet unclear mechanisms. We tested whether FAK is functionally important for muscle hypertrophy, with the hypothesis that FAK knockdown (FAK-KD) would impede cell growth associated with a trophic stimulus. C2C12 skeletal muscle c...

Background: The endogenous opioid peptide, nociception (Noc), contributes to the regulation of systemic blood pressure and regional blood flow. Recent clinical and animal studies have reported that Noc and its receptor (nociceptin/orphanin FQ [NOP]) are involved in inflammation and sepsis. The purpose of the present study was to examine the modula...