Alberto Rossi

Muscle type and fiber type specificity in muscle wasting.

Muscle wasting occurs in a variety of conditions, including both genetic diseases, such as muscular dystrophies, and acquired disorders, ranging from muscle disuse to cancer cachexia, from heart failure to aging sarcopenia. In most of these conditions, the loss of muscle tissue is not homogeneous, but involves specific muscle groups, for example Duchenne muscular dystrophy affects most body muscles but spares extraocular muscles, and other dystrophies affect selectively proximal or distal limb muscles. In addition, muscle atrophy can affect specific fiber types, involving predominantly slow type 1 or fast type 2 muscle fibers, and is frequently accompanied by a slow-to-fast or fast-to-slow fiber type shift. For example, muscle disuse, such as spinal cord injury, causes type 1 fiber atrophy with a slow-to-fast fiber type shift, whereas cancer cachexia leads to preferential atrophy of type 2 fibers with a fast-to-slow fiber type shift. The identification of the signaling pathways responsible for the differential response of muscles types and fiber types can lead to a better understanding of the pathogenesis of muscle wasting and to the design of therapeutic interventions appropriate for the specific disorders. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting.

Two novel/ancient myosins in mammalian skeletal muscles: MYH14/7b and MYH15 are expressed in extraocular muscles and muscle spindles

The mammalian genome contains three ancient sarcomeric myosin heavy chain (MYH) genes, MYH14/7b, MYH15 and MYH16, in addition to the two well characterized clusters of skeletal and cardiac MYHs. MYH16 is expressed in jaw muscles of carnivores; however the expression pattern of MYH14 and MYH15 is not known. MYH14 and MYH15 orthologues are present in frogs and birds, coding for chicken slow myosin 2 and ventricular MYH, respectively, whereas only MYH14 orthologues have been detected in fish. In all species the MYH14 gene contains a microRNA, miR‐499. Here we report that in rat and mouse, MYH14 and miR‐499 transcripts are detected in heart, slow muscles and extraocular (EO) muscles, whereas MYH15 transcripts are detected exclusively in EO muscles. However, MYH14 protein is detected only in a minor fibre population in EO muscles, corresponding to slow‐tonic fibres, and in bag fibres of muscle spindles. MYH15 protein is present in most fibres of the orbital layer of EO muscles and in the extracapsular region of bag fibres. During development, MYH14 is expressed at low levels in skeletal muscles, heart and all EO muscle fibres but disappears from most fibres, except the slow‐tonic fibres, after birth. In contrast, MYH15 is absent in embryonic and fetal muscles and is first detected after birth in the orbital layer of EO muscles. The identification of the expression pattern of MYH14 and MYH15 brings to completion the inventory of the MYH isoforms involved in sarcomeric architecture of skeletal muscles and provides an unambiguous molecular basis to study the contractile properties of slow‐tonic fibres in mammals.

Blood pressure changes during heavy-resistance exercise.

To study the mechanisms of the blood pressure changes during weight-lifting, three hypertensive and five normotensive body-builders underwent continuous intra-arterial monitoring. In two subjects (one normotensive and one hypertensive), intrathoracic and intra-abdominal pressures were also measured. Extremely high blood pressure elevations of up to 345/245 mmHg were observed during the lifts. Squatting caused the highest pressure rises and single-arm curls the lowest. Both the intrathoracic and the intra-abdominal pressures increased greatly during each lift and closely paralleled the changes in intra-arterial pressure. A close correlation was found between the blood pressure increase during the exercise and during a hand-grip test (r = 0.95, P less than 0.001). These results suggest that a pronounced increase in intra-thoracic and intra-abdominal pressures is a major determinant of the blood pressure elevations occurring during weight-lifting. The pressor reflex which accompanies static contractions and the individual baseline blood pressure levels also seem to affect the height of the pressure peaks.

Developmental myosins: expression patterns and functional significance

Developing skeletal muscles express unique myosin isoforms, including embryonic and neonatal myosin heavy chains, coded by the myosin heavy chain 3 (MYH3) and MYH8 genes, respectively, and myosin light chain 1 embryonic/atrial, encoded by the myosin light chain 4 (MYL4) gene. These myosin isoforms are transiently expressed during embryonic and fetal development and disappear shortly after birth when adult fast and slow myosins become prevalent. However, developmental myosins persist throughout adult stages in specialized muscles, such as the extraocular and jaw-closing muscles, and in the intrafusal fibers of the muscle spindles. These myosins are re-expressed during muscle regeneration and provide a specific marker of regenerating fibers in the pathologic skeletal muscle. Mutations in MYH3 or MYH8 are responsible for distal arthrogryposis syndromes, characterized by congenital joint contractures and orofacial dysmorphisms, supporting the importance of muscle contractile activity and body movements in joint development and in shaping the form of the face during fetal development. The biochemical and biophysical properties of developmental myosins have only partially been defined, and their functional significance is not yet clear. One possibility is that these myosins are specialized in contracting against low loads, and thus, they may be adapted to the prenatal environment, when fetal muscles contract against a very low load compared to postnatal muscles.

Hypertensive Cerebrovascular Disease and the Renin-Angiotensin System

BACKGROUND Arterial hypertension is the leading cause of cardiovascular disease and is associated with an increased risk of stroke and heart attack. These complications have been largely attributed to the remodeling of the arterial wall, including accelerated atherosclerosis occurring in hypertensive patients. Although the risk of haemorrhagic stroke seems to be directly related to the level of blood pressure elevation, no such tight relationship has been found between blood pressure levels and atherosclerosis. This observation has led to the concept that a number of genetic, humoral, and cellular factors may be involved in atherogenesis in hypertensive patients. SUMMARY OF REVIEW The experimental and clinical evidence concerning the role of the renin-angiotensin system in cardiovascular remodeling and atherogenesis of the cerebrovascular bed as well as the data supporting an association between angiotensin II and thrombotic stroke are examined. CONCLUSIONS The contribution of the renin-angiotensin system to the pathogenesis of accelerated carotid artery atherosclerosis and particularly of cerebrovascular disease remains to be definitively proven. However, the bulk of experimental and clinical data are consistent with the hypothesis that the renin-angiotensin system may play a detrimental role.

Carotid artery lesions in patients with nondiabetic chronic renal failure

Atherosclerotic complications are the leading cause of death in chronic renal failure (CRF) patients. Therefore, we wished to investigate the prevalence of carotid artery lesions (CALs) in these subjects. Two groups were evaluated by high-resolution echo Doppler: group 1 included 103 patients (68 males and 35 females) affected by nonnephrotic CRF and group 2 included 100 control subjects (60 males and 40 females). The prevalence of hypertension was 84% in both groups. The exclusion criteria included diabetes mellitus and symptoms of cerebrovascular disease. In the two groups we evaluated clinical history, physical examination, total cholesterol, triglycerides, fibrinogen, blood cell counts, blood urea nitrogen, creatinine, 24-hour proteinuria, and urine analysis. In group 1 patients the following lipid profile parameters were also evaluated: low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, lipoprotein(a), ApoAI, ApoAII, and ApoB. Group 1 had higher triglycerides and fibrinogen than group 2. A lower body mass index was found in group 1 than in group 2. The prevalence of CALs was significantly higher in the CRF patients than in the control subjects (62% v 47%; P = 0.04). The difference between the two groups was more striking among normotensive patients (62% v 19%; P = 0.03). All CRF patients affected by peripheral arterial disease and 86% of those having coronary artery disease had associated CALs. In CRF patients the severity of CALs was positively correlated to age, white blood cell count, triglycerides, and fibrinogen. Nondiabetic CRF patients have a higher prevalence of carotid artery lesions than control subjects. Several factors besides hypertension, including lipids, blood coagulation, and leukocytes, could contribute to the accelerated atherosclerosis of CRF patients.

The renin-angiotensin-aldosterone system and carotid artery disease in mild-to-moderate primary hypertension.

Background The evidence linking activation of the renin— angiotensin system with accelerated cerebro-vascular atherosclerosis remains controversial. We therefore prospectively investigated the relationships of plasma renin activity and aldosterone levels with carotid artery lesions (CAL) in essential hypertension. Methods We evaluated the prevalence and severity of CAL and the intimal—medial thickness (IMT) with a high-resolution echo-Doppler technique in 107 cerebrovascularly asymptomatic consecutive primary hypertensives (55 male, 52 female) and in 70 (42 male, 28 female) normotensive controls. We also measured supine plasma renin activity (PRA) and aldosterone before and 45 min after captopril administration, while daily urinary excretion of sodium was measured. Results Both the prevalence (59.4 versus 26.2%) and severity of sex- and age-adjusted and unadjusted CAL and IMT were significantly higher in hypertensives than in controls. Regression analysis showed different predictors of IMT (age and captopril-stimulated-PRA, R2 = 0.27, P < 0.0001), score of CAL (mean blood pressure, R2 = 0.15, F = 12.73, P < 0.0001) and maximal stenosis (pulse pressure and known duration of hypertension R2 = 0.29, F = 14.58, P < 0.0001). Sex- and age-adjusted IMT did not differ between quartiles of renin-sodium profile. However, patients in the quartile with the highest PRA had the lowest score of CAL and an inverse relationship between age-adjusted PRA and IMT and CAL was found. Conclusions These results, besides confirming an association of both IMT and CAL with primary hypertension and ageing, demonstrate that CAL and IMT have different correlates. However, they do not support the contention that a high renin-sodium profile carries an excess risk of CAL in primary hypertensives with no clinical evidence of cerebro-vascular disease.

Clinical Assessment of Low Molecular Weight Heparin Effects in Peripheral Vascular Disease

This study was carried out, using the double-blind method vs placebo, on 36 patients suffering from stage II peripheral vascular disease (PVD) according to Leriche, to check the clinical and hemorrheologic effects of the administration of a new low molecular weight heparin (LMWH). After a one-month washout period, the patients were randomly assigned either to the group treated with the LMWH (15,000 aXaU/day sc) or to the group treated with indistinguishable placebo. At the start of the study and after three and six months of treatment, clini cal, instrumental, and laboratory tests were performed to assess local and sys temic efficacy and tolerance. The LMWH under study caused a statistically significant increase in claudi cation time, with a parallel increase in the absolute claudication distance and in the interval free of pain. The drug also led to a significant increase in activated partial thromboplastin time, the values of which, however, remained within the normal limits, and to a marked reduction in blood viscosity. No significant vari ation was observed in the tolerability parameters in the two treatment groups, and no local or systemic adverse reactions occurred.

Relationship of Early Carotid Artery Disease With Lipoprotein (a), Apolipoprotein B, and Fibrinogen in Asymptomatic Essential Hypertensive Patients and Normotensive Subjects

Abstract Background We investigated the relationships between plasma lipids and lipoprotein fractions and carotid artery lesions (CAL) in 177 cerebro-vascularly asymptomatic subjects, of whom 107 were primary hypertensive patients and 70 normotensive controls. Methods The prevalence and severity of CAL, as assessed by calculating a score of severity (score of CAL) and the maximal stenosis of both sides, as well as the intimal-medial thickness (IMT) were evaluated with a high-resolution echo-Doppler technique. We measured total serum cholesterol, triglycerides, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, lipoprotein (a) [Lp(a)], Apo (apolipoprotein)AI, ApoAII, ApoB, and fibrinogen. Results Both the prevalence (59.4% vs 26.2%) and severity of sex- and age-adjusted and unadjusted CAL and IMT were significantly higher in hypertensive patients than in controls. Regression analysis showed different predictors of IMT and maximal stenosis. The variables that remained in the model were age, mean blood pressure (BP), and smoking for IMT; pulse pressure, known duration of hypertension (HT), fibrinogen, and ApoB for the score of CAL; and the last four variables along with age and mean BP for maximal stenosis. Furthermore, we identified a link between the atherogenic lipoprotein fractions Lp(a) and ApoB, fibrinogen and early carotid artery atherosclerotic changes. Conclusions The different correlates of IMT, CAL, and maximal degree of stenosis suggest that they reflect different events occurring in the arterial wall in response to aging, HT, and other risk factors, rather than simply different stages of the same atherosclerotic process.

Insufficienza renale cronica e danno carotideo

* Hanno parteciparo a questa studio : A. AntoneI/o, L. Calo, A. Giacomini. M. Normanno, L. Maldin i. M. Fusaro. V. Bordin. e. Abaterusso , E. De Vivo (Divis ione di Nefro logia la , Univers ita degli Studi di Padova ); A. Calabro. M.L. Calabro , D . Bianchi, E. Abbruzzese (Patologia Medica la oUnivers ita degli Studi di Padova): R. Cavagna, L. De Silves tro (Serviz io di Nefro logia e Dialisi , Ospedale di Belluno); A. Bonadonna . S. Mastrosimone (Servi zio di Nefro logia e Dialisi. Ospedale di Camposampiero)