Incidence of heterotopic ossification following total hip arthroplasty by approach: a systematic review.

BACKGROUND: Heterotopic ossification (HO) formation has been increasingly recognized as a complication of major orthopedic surgeries, particularly total hip arthroplasty (THA). Though, the overall incidence of HO following THA has been well-documented, it is often not reported by severity or by surgical approach. QUESTIONS/PURPOSES: (1) What are the demographics of patients with HO? (2) What is the severity of HO following THA using the Brooker classification? (3) What is the incidence and class of HO following different THA approaches (anterior, posterior, posterolateral, anterolateral, superior, lateral, trans-gluteal)? (4) What are the number and training level of surgeons who performed each procedure? METHODS: The PubMed, Embase, and Web of Science databases were queried, and PRISMA guidelines were followed. Qualitative and quantitative analyses were performed using Microsoft Excel. RESULTS: We isolated 26 studies evaluating 6512 total hip arthroplasties (THA). The mean HO percentage overall was 28.8%, mostly Class I (54.2%) or Class II (29.6%). The highest percentage of HO was associated with the modified direct lateral (57.2%) and the traditional lateral (34.6%) approaches. The lowest HO percentages were identified following posterolateral (12.8%) and direct superior approaches (1%). Most studies reported a singular senior surgeon operating within the same approach for all patients. CONCLUSIONS: The traditional lateral and modified direct lateral approaches to THA resulted in the highest percentage of HO postoperatively. However, most ossification cases were not clinically significant and did not strongly affect overall patient morbidity. Further studies are warranted to identify an association between severity of ossification and different arthroplasty approaches.

Combined overexpression of SIRT1 and knockout of GCN5 in adult skeletal muscle does not affect glucose homeostasis or exercise performance in mice.

Sirtuin 1 (SIRT1) and general control of amino acid synthesis 5 (GCN5) regulate mitochondrial biogenesis via opposing modulation of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) acetylation status and activity. However, the combined contribution of SIRT1 and GCN5 to skeletal muscle metabolism and endurance performance in vivo is unknown. In this study, we investigated the impact of combined skeletal muscle-specific overexpression of SIRT1 and deletion of GCN5 on glucose homeostasis, skeletal muscle mitochondrial biogenesis and function, and metabolic adaptation to endurance exercise training in mice. We generated mice with combined and tamoxifen-inducible skeletal muscle-specific overexpression of SIRT1 and knockout of GCN5 (dTG) and floxed [wild type (WT)] littermates using a Cre-LoxP approach. All mice were treated with tamoxifen at 5-6 wk of age, and 4-7 wk later glucose homeostasis, skeletal muscle contractile function, mitochondrial function, and the effects of 14 days of voluntary wheel running on expression of metabolic proteins and exercise capacity were assessed. There was no difference in oral glucose tolerance, skeletal muscle contractile function, mitochondrial abundance, or maximal respiratory capacity between dTG and WT mice. Additionally, there were no genotype differences in exercise performance and markers of mitochondrial biogenesis after 14 days of voluntary wheel running. These results demonstrate that combined overexpression of SIRT1 and loss of GCN5 in vivo does not promote metabolic remodeling in skeletal muscle of sedentary or exercise-trained mice.

Germline or inducible knockout of p300 or CBP in skeletal muscle does not alter insulin sensitivity.

Akt is a critical mediator of insulin-stimulated glucose uptake in skeletal muscle. The acetyltransferases, E1A binding protein p300 (p300) and cAMP response element-binding protein binding protein (CBP) are phosphorylated and activated by Akt, and p300/CBP can acetylate and inactivate Akt, thus giving rise to a possible Akt-p300/CBP axis. Our objective was to determine the importance of p300 and CBP to skeletal muscle insulin sensitivity. We used Cre-LoxP methodology to generate mice with germline [muscle creatine kinase promoter (P-MCK and C-MCK)] or inducible [tamoxifen-activated, human skeletal actin promoter (P-iHSA and C-iHSA)] knockout of p300 or CBP. A subset of P-MCK and C-MCK mice were switched to a calorie-restriction diet (60% of ad libitum intake) or high-fat diet at 10 wk of age. For P-iHSA and C-iHSA mice, knockout was induced at 10 wk of age. At 13-15 wk of age, we measured whole-body energy expenditure, oral glucose tolerance, and/or ex vivo skeletal muscle insulin sensitivity. Although p300 and CBP protein abundance and mRNA expression were reduced 55%-90% in p300 and CBP knockout mice, there were no genotype differences in energy expenditure or fasting glucose and insulin concentrations. Moreover, neither loss of p300 or CBP impacted oral glucose tolerance or skeletal muscle insulin sensitivity, nor did their loss impact alterations in these parameters in response to a calorie restriction or high-fat diet. Muscle-specific loss of either p300 or CBP, be it germline or in adulthood, does not impact energy expenditure, glucose tolerance, or skeletal muscle insulin action.

Defining the contribution of skeletal muscle pyruvate dehydrogenase α1 to exercise performance and insulin action.

The pyruvate dehydrogenase complex (PDC) converts pyruvate to acetyl-CoA and is an important control point for carbohydrate (CHO) oxidation. However, the importance of the PDC and CHO oxidation to muscle metabolism and exercise performance, particularly during prolonged or high-intensity exercise, has not been fully defined especially in mature skeletal muscle. To this end, we determined whether skeletal muscle-specific loss of pyruvate dehydrogenase alpha 1 ( Pdha1), which is a critical subunit of the PDC, impacts resting energy metabolism, exercise performance, or metabolic adaptation to high-fat diet (HFD) feeding. For this, we generated a tamoxifen (TMX)-inducible Pdha1 knockout (PDHmKO) mouse, in which PDC activity is temporally and specifically ablated in adult skeletal muscle. We assessed energy expenditure, ex vivo muscle contractile performance, and endurance exercise capacity in PDHmKO mice and wild-type (WT) littermates. Additionally, we studied glucose homeostasis and insulin sensitivity in muscle after 12 wk of HFD feeding. TMX administration largely ablated PDHα in skeletal muscle of adult PDHmKO mice but did not impact energy expenditure, muscle contractile function, or low-intensity exercise performance. Additionally, there were no differences in muscle insulin sensitivity or body composition in PDHmKO mice fed a control or HFD, as compared with WT mice. However, exercise capacity during high-intensity exercise was severely impaired in PDHmKO mice, in parallel with a large increase in plasma lactate concentration. In conclusion, although skeletal muscle PDC is not a major contributor to resting energy expenditure or long-duration, low-intensity exercise performance, it is necessary for optimal performance during high-intensity exercise.

p300 and cAMP response element-binding protein-binding protein in skeletal muscle homeostasis, contractile function, and survival.

BACKGROUND: Reversible ε-amino acetylation of lysine residues regulates transcription as well as metabolic flux; however, roles for specific lysine acetyltransferases in skeletal muscle physiology and function are unknown. In this study, we investigated the role of the related acetyltransferases p300 and cAMP response element-binding protein-binding protein (CBP) in skeletal muscle transcriptional homeostasis and physiology in adult mice. METHODS: Mice with skeletal muscle-specific and inducible knockout of p300 and CBP (PCKO) were generated by crossing mice with a tamoxifen-inducible Cre recombinase expressed under the human α-skeletal actin promoter with mice having LoxP sites flanking exon 9 of the Ep300 and Crebbp genes. Knockout of PCKO was induced at 13-15 weeks of age via oral gavage of tamoxifen for 5 days to both PCKO and littermate control [wildtype (WT)] mice. Body composition, food intake, and muscle function were assessed on day 0 (D0) through 5 (D5). Microarray and tandem mass tag mass spectrometry analyses were performed to assess global RNA and protein levels in skeletal muscle of PCKO and WT mice. RESULTS: At D5 after initiating tamoxifen treatment, there was a reduction in body weight (-15%), food intake (-78%), stride length (-46%), and grip strength (-45%) in PCKO compared with WT mice. Additionally, ex vivo contractile function [tetanic tension (kPa)] was severely impaired in PCKO vs. WT mice at D3 (~70-80% lower) and D5 (~80-95% lower) and resulted in lethality within 1 week-a phenotype that is reversed by the presence of a single allele of either p300 or CBP. The impaired muscle function in PCKO mice was paralleled by substantial transcriptional alterations (3310 genes; false discovery rate < 0.1), especially in gene networks central to muscle contraction and structural integrity. This transcriptional uncoupling was accompanied by changes in protein expression patterns indicative of impaired muscle function, albeit to a smaller magnitude (446 proteins; fold-change > 1.25; false discovery rate < 0.1). CONCLUSIONS: These data reveal that p300 and CBP are required for the control and maintenance of contractile function and transcriptional homeostasis in skeletal muscle and, ultimately, organism survival. By extension, modulating p300/CBP function may hold promise for the treatment of disorders characterized by impaired contractile function in humans.

Skeletal muscle mitochondrial function and exercise capacity are not impaired in mice with knockout of STAT3.

Signal transducer and activator of transcription 3 (STAT3) was recently found to be localized to mitochondria in a number of tissues and cell types, where it modulates oxidative phosphorylation via interactions with the electron transport proteins, complex I and complex II. Skeletal muscle is densely populated with mitochondria although whether STAT3 contributes to skeletal muscle oxidative capacity is unknown. In the present study, we sought to elucidate the contribution of STAT3 to mitochondrial and skeletal muscle function by studying mice with muscle-specific knockout of STAT3 (mKO). First, we developed a novel flow cytometry-based approach to confirm that STAT3 is present in skeletal muscle mitochondria. However, contrary to findings in other tissue types, complex I and complex II activity and maximal mitochondrial respiratory capacity in skeletal muscle were comparable between mKO mice and floxed/wild-type littermates. Moreover, there were no genotype differences in endurance exercise performance, skeletal muscle force-generating capacity, or the adaptive response of skeletal muscle to voluntary wheel running. Collectively, although we confirm the presence of STAT3 in skeletal muscle mitochondria, our data establish that STAT3 is dispensable for mitochondrial and physiological function in skeletal muscle.NEW & NOTEWORTHY Whether signal transducer and activator of transcription 3 (STAT3) can regulate the activity of complex I and II of the electron transport chain and mitochondrial oxidative capacity in skeletal muscle, as it can in other tissues, is unknown. By using a mouse model lacking STAT3 in muscle, we demonstrate that skeletal muscle mitochondrial and physiological function, both in vivo and ex vivo, is not impacted by the loss of STAT3.

Calorie Restriction-Induced Increase in Skeletal Muscle Insulin Sensitivity Is Not Prevented by Overexpression of the p55α Subunit of Phosphoinositide 3-Kinase.

Introduction: The Phosphoinositide 3-kinase (PI3K) signaling pathway plays an important role in skeletal muscle insulin-stimulated glucose uptake. While whole-body and tissue specific knockout (KO) of individual or combinations of the regulatory subunits of PI3K (p85α, p55α, and p50α or p85ß); increase insulin sensitivity, no study has examined whether increasing the expression of the individual regulatory subunits would inhibit insulin action in vivo. Therefore, the objective of this study was to determine whether skeletal muscle-specific overexpression of the p55α regulatory subunit of PI3K impairs skeletal muscle insulin sensitivity, or prevents its enhancement by caloric restriction. Methods: We developed a novel "floxed" mouse that, through the Cre-LoxP approach, allows for tamoxifen (TMX)-inducible and skeletal muscle-specific overexpression of the p55α subunit of PI3K (referred to as, 'p55α-mOX'). Beginning at 10 weeks of age, p55α-mOX mice and their floxed littermates (referred to as wildtype [WT]) either continued with free access to food (ad libitum; AL), or were switched to a calorie restricted diet (CR; 60% of AL intake) for 20 days. We measured body composition, whole-body energy expenditure, oral glucose tolerance and ex vivo skeletal muscle insulin sensitivity in isolated soleus and extensor digitorum longus muscles using the 2-deoxy-glucose (2DOG) uptake method. Results: p55α mRNA and protein expression was increased ∼2 fold in muscle from p55α-mOX versus WT mice. There were no differences in energy expenditure, total activity, or food intake of AL-fed mice between genotypes. Body weight, fat and lean mass, tissue weights, and fasting glucose and insulin were comparable between p55α-mOX and WT mice on AL, and were decreased equally by CR. Interestingly, overexpression of p55α did not impair oral glucose tolerance or skeletal muscle insulin signaling or sensitivity, nor did it impact the ability of CR to enhance these parameters. Conclusion: Skeletal muscle-specific overexpression of p55α does not impact skeletal muscle insulin action, suggesting that p85α and/or p50α may be more important regulators of skeletal muscle insulin signaling and sensitivity.