The Loss of Tafazzin Transacetylase Activity Is Sufficient to Drive Testicular Infertility.

Barth syndrome (BTHS) is a rare, infantile-onset, X-linked mitochondriopathy exhibiting a variable presentation of failure to thrive, growth insufficiency, skeletal myopathy, neutropenia, and heart anomalies due to mitochondrial dysfunction secondary to inherited TAFAZZIN transacetylase mutations. Although not reported in BTHS patients, male infertility is observed in several () mouse alleles and in a mutant. Herein, we examined the male infertility phenotype in a BTHS-patient-derived point-mutant knockin mouse () allele that expresses a mutant protein lacking transacetylase activity.

Coordination between the eIF2 kinase GCN2 and p53 signaling supports purine metabolism and the progression of prostate cancer.

Cancers invoke various pathways to mitigate external and internal stresses to continue their growth and progression. We previously reported that the eIF2 kinase GCN2 and the integrated stress response are constitutively active in prostate cancer (PCa) and are required to maintain amino acid homeostasis needed to fuel tumor growth. However, although loss of GCN2 function reduces intracellular amino acid availability and PCa growth, there is no appreciable cell death.

Sucla2 Knock-Out in Skeletal Muscle Yields Mouse Model of Mitochondrial Myopathy With Muscle Type-Specific Phenotypes.

Background: Pathogenic variants in subunits of succinyl-CoA synthetase (SCS) are associated with mitochondrial encephalomyopathy in humans. SCS catalyses the conversion of succinyl-CoA to succinate coupled with substrate-level phosphorylation of either ADP or GDP in the TCA cycle. This report presents a muscle-specific conditional knock-out (KO) mouse model of Sucla2, the ADP-specific beta subunit of SCS, generating a novel in vivo model of mitochondrial myopathy.

A Barth Syndrome Patient-Derived Point Mutation in Drives Progressive Cardiomyopathy in Mice.

Cardiomyopathy is the predominant defect in Barth syndrome (BTHS) and is caused by a mutation of the X-linked gene, which encodes an enzyme responsible for remodeling mitochondrial cardiolipin. Despite the known importance of mitochondrial dysfunction in BTHS, how specific mutations cause diverse BTHS heart phenotypes remains poorly understood. We generated a patient-tailored knock-in mouse allele () that phenocopies BTHS clinical traits.

Sex-specific increases in myostatin and SMAD3 contribute to obesity-related insulin resistance in human skeletal muscle and primary human myotubes.

The purpose of the present study was to determine the effects of obesity and biological sex on myostatin expression in humans and to examine the direct effects of myostatin, SMAD2, and SMAD3 on insulin signaling in primary human skeletal muscle cells (HSkMCs). For , 15 lean [body mass index (BMI): 22.1 ± 0.

Uric acid formation is driven by crosstalk between skeletal muscle and other cell types.

Hyperuricemia is implicated in numerous pathologies, but the mechanisms underlying uric acid production are poorly understood. Using a combination of mouse studies, cell culture studies, and human serum samples, we sought to determine the cellular source of uric acid. In mice, fasting and glucocorticoid treatment increased serum uric acid and uric acid release from ex vivo-incubated skeletal muscle.

Clinical trials in Charcot-Marie-Tooth disorders: a retrospective and preclinical assessment.

Objective: This study aimed to evaluate the progression of clinical and preclinical trials in Charcot-Marie-Tooth (CMT) disorders.

Background: CMT has historically been managed symptomatically and with genetic counseling. The evolution of molecular and pathologic understanding holds a therapeutic promise in gene-targeted therapies.

FoxO3 normalizes Smad3-induced arterial smooth muscle cell growth.

Transition of arterial smooth muscle (ASM) from a quiescent, contractile state to a growth-promoting state is a hallmark of cardiovascular disease (CVD), a leading cause of death and disability in the United States and worldwide. While many individual signals have been identified as important mechanisms in this phenotypic conversion, the combined impact of the transcription factors Smad3 and FoxO3 in ASM growth is not known. The purpose of this study was to determine that a coordinated, phosphorylation-specific relationship exists between Smad3 and FoxO3 in the control of ASM cell growth.

Creatine Kinase Equilibration and ΔG over an Extended Range of Physiological Conditions: Implications for Cellular Energetics, Signaling, and Muscle Performance.

In this report, we establish a straightforward method for estimating the equilibrium constant for the creatine kinase reaction (CK K″) over wide but physiologically and experimentally relevant ranges of pH, Mg and temperature. Our empirical formula for CK K″ is based on experimental measurements. It can be used to estimate [ADP] when [ADP] is below the resolution of experimental measurements, a typical situation because [ADP] is on the order of micromolar concentrations in living cells and may be much lower in many in vitro experiments.

CaMKK2 is not involved in contraction-stimulated AMPK activation and glucose uptake in skeletal muscle.

Objective: The AMP-activated protein kinase (AMPK) gets activated in response to energetic stress such as contractions and plays a vital role in regulating various metabolic processes such as insulin-independent glucose uptake in skeletal muscle. The main upstream kinase that activates AMPK through phosphorylation of α-AMPK Thr172 in skeletal muscle is LKB1, however some studies have suggested that Ca/calmodulin-dependent protein kinase kinase 2 (CaMKK2) acts as an alternative kinase to activate AMPK. We aimed to establish whether CaMKK2 is involved in activation of AMPK and promotion of glucose uptake following contractions in skeletal muscle.

Hypoxia Resistance Is an Inherent Phenotype of the Mouse Flexor Digitorum Brevis Skeletal Muscle.

The various functions of skeletal muscle (movement, respiration, thermogenesis, etc.) require the presence of oxygen (O). Inadequate O bioavailability (ie, hypoxia) is detrimental to muscle function and, in chronic cases, can result in muscle wasting.

Platelet-Rich Plasma Injection for Thumb Carpometacarpal Joint Osteoarthritis.

Objective: To assess the effects of platelet-rich plasma (PRP) injection among patients with thumb carpometacarpal (CMC) joint osteoarthritis (OA).

Design: Retrospective chart review with follow-up questionnaires/surveys. Post-procedure, patients were sent standardized, automatically-generated follow-up questionnaires, and contacted for a survey regarding patient-reported outcomes.

Efficacy and safety of Tuina for chronic nonspecific low back pain: A PRISMA-compliant systematic review and meta-analysis.

Objective: Chronic nonspecific low back pain (CNLBP) is a serious medical and social problem resulting in functional decline and decreased work ability. Tuina, a form of manual therapy, has been sparsely used to treat patients with CNLBP. To systematically assess the efficacy and safety of Tuina for patients with CNLBP.

Calcific Tendinitis of the Proximal Flexor Carpi Radialis in a Throwing Athlete.

Flexor carpi radialis tendinitis is a condition that almost exclusively affects the distal aspect of the tendon where it lies in a tight fibro-osseous tunnel. Tendinitis of the proximal aspect of the tendon at its myotendinous junction is extremely rare. Herein, we present a single case of calcific tendinitis of the flexor carpi radialis tendon at its myotendinous junction in a throwing athlete.

Peroxisome proliferator-activated receptor γ coactivator 1-α overexpression improves angiogenic signalling potential of skeletal muscle-derived extracellular vesicles.

New Findings: What is the central question of this study? Skeletal muscle extracellular vesicles likely act as pro-angiogenic signalling factors: does overexpression of peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) alter skeletal muscle myotube extracellular vesicle release, contents and angiogenic potential? What is the main finding and its importance? Overexpression of PGC-1α results in secretion of extracellular vesicles that elevate measures of angiogenesis and protect against acute oxidative stress in vitro. Skeletal muscle with high levels of PGC-1α expression, commonly associated with exercise induced angiogenesis and high basal capillarization, may secrete extracellular vesicles that support capillary growth and maintenance.

Abstract: Skeletal muscle capillarization is proportional to muscle fibre mitochondrial content and oxidative capacity.

Skeletal muscle contraction kinetics and AMPK responses are modulated by the adenine nucleotide degrading enzyme AMPD1.

AMP deaminase 1 (AMPD1; AMP → IMP + NH) deficiency in skeletal muscle results in an inordinate accumulation of AMP during strenuous exercise, with some but not all studies reporting premature fatigue and reduced work capacity. To further explore these inconsistencies, we investigated the extent to which AMPD1 deficiency impacts skeletal muscle contractile function of different muscles and the [AMP]/AMPK responses to different intensities of fatiguing contractions. To reduce AMPD1 protein, we electroporated either an inhibitory AMPD1-specific miRNA encoding plasmid or a control plasmid, into contralateral EDL and SOL muscles of C57BL/6J mice ( = 48 males, 24 females).

Intrinsic adaptations in OXPHOS power output and reduced tumorigenicity characterize doxorubicin resistant ovarian cancer cells.

Although the development of chemoresistance is multifactorial, active chemotherapeutic efflux driven by upregulations in ATP binding cassette (ABC) transporters are commonplace. Chemotherapeutic efflux pumps, like ABCB1, couple drug efflux to ATP hydrolysis and thus potentially elevate cellular demand for ATP resynthesis. Elevations in both mitochondrial content and cellular respiration are common phenotypes accompanying many models of cancer cell chemoresistance, including those dependent on ABCB1.

Passive wrist deviation to increase the ultrasound identified procedural safe zone in carpal tunnel syndrome: A retrospective cohort study.

Introduction: Carpal tunnel syndrome (CTS) is the most common peripheral nerve entrapment syndrome. Although prior studies have explored the anatomic changes of the median nerve and carpal arch with different wrist deviations and positionings, the change in safe zone distance between the median nerve and ulnar artery with ulnar or radial wrist deviations has not been adequately investigated.

Objective: To identify the optimal wrist positioning that increases the safe zone distance between the median nerve and ulnar artery using ultrasound in patients with CTS.

Utility of Carpal Tunnel Release and Ulnar Decompression in CMT1A and HNPP.

Introduction/aims: Carpal and cubital tunnel syndrome (CTS, CuTS) are common among patients with hereditary neuropathy with liability to pressure-palsies (HNPP) and Charcot-Marie-Tooth type 1A (CMT1A) and may impact quality of life. We aimed to evaluate the utility of nerve decompression surgeries in these patients.

Methods: Medical records were reviewed for patients with PMP22 mutations confirmed in Mayo Clinic laboratories from January 1999 to December 2020, who had CTS and CuTS and underwent surgical decompression.

Liquid chromatography method for simultaneous quantification of ATP and its degradation products compatible with both UV-Vis and mass spectrometry.

ATP and its degradation products are essential metabolic and signaling molecules. Traditionally, they have been quantified via high-performance liquid chromatography (HPLC) with UV-Vis detection while utilizing phosphate buffer mobile phase, but this approach is incompatible with modern mass detection. The goal of this study was to develop an ultra-performance liquid chromatography (UPLC) method free of phosphate buffer, to allow for analysis of adenine nucleotides with UV-Vis and mass spectrometry (MS) simultaneously.

Return to work following ultrasound guided thread carpal tunnel release versus open carpal tunnel release: a comparative study.

A retrospective review of hospital employees at a single employer institution who underwent ultrasound guided thread carpal tunnel release (TCTR) or open carpal tunnel release (OCTR) between January 2018 and August 2020 was performed to ascertain differences in return-to-work status. Patient age, sex, occupation, handedness, severity of carpal tunnel syndrome, prior treatments and surgical outcomes were reviewed. A total of 18 patients underwent TCTR and 17 patients underwent OCTR.

AMP deamination is sufficient to replicate an atrophy-like metabolic phenotype in skeletal muscle.

Background: Skeletal muscle atrophy, whether caused by chronic disease, acute critical illness, disuse or aging, is characterized by tissue-specific decrease in oxidative capacity and broad alterations in metabolism that contribute to functional decline. However, the underlying mechanisms responsible for these metabolic changes are largely unknown. One of the most highly upregulated genes in atrophic muscle is AMP deaminase 3 (AMPD3: AMP → IMP + NH), which controls the content of intracellular adenine nucleotides (AdN; ATP + ADP + AMP).