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Pietrangelo L.,University of Chieti Pescara | D'Incecco A.,University of Chieti Pescara | Ainbinder A.,University of Rochester | Michelucci A.,University of Chieti Pescara | And 4 more authors.
Oncotarget | Year: 2015

Calcium release units (CRUs) and mitochondria control myoplasmic [Ca2+] levels and ATP production in muscle, respectively. We recently reported that these two organelles are structurally connected by tethers, which promote proximity and proper Ca2+ signaling. Here we show that disposition, ultrastructure, and density of CRUs and mitochondria and their reciprocal association are compromised in muscle from aged mice. Specifically, the density of CRUs and mitochondria is decreased in muscle fibers from aged (>24 months) vs. adult (3-12 months), with an increased percentage of mitochondria being damaged and misplaced from their normal triadic position. A significant reduction in tether (13.8±0.4 vs. 5.5±0.3 tethers/100μm2) and CRUmitochondrial pair density (37.4±0.8 vs. 27.0±0.7 pairs/100μm2) was also observed in aged mice. In addition, myoplasmic Ca2+ transient (1.68±0.08 vs 1.37±0.03) and mitochondrial Ca2+ uptake (9.6±0.050 vs 6.58±0.54) during repetitive high frequency tetanic stimulation were significantly decreased. Finally oxidative stress, assessed from levels of 3-nitrotyrosine (3-NT), Cu/Zn superoxide-dismutase (SOD1) and Mn superoxide dismutase (SOD2) expression, were significantly increased in aged mice. The reduced association between CRUs and mitochondria with aging may contribute to impaired cross-talk between the two organelles, possibly resulting in reduced efficiency in activity-dependent ATP production and, thus, to age-dependent decline of skeletal muscle performance.

Carnio S.,Venetian Institute of Molecular Medicine | LoVerso F.,Venetian Institute of Molecular Medicine | Baraibar M.,University Pierre and Marie Curie | Longa E.,University of Pavia | And 17 more authors.
Cell Reports | Year: 2014

The cellular basis of age-related tissue deterioration remains largely obscure. The ability to activate compensatory mechanisms in response to environmental stress is an important factor for survival and maintenance of cellular functions. Autophagy is activated both under short and prolonged stress and is required to clear the cell of dysfunctional organelles and altered proteins. We report that specific autophagy inhibition in muscle has a major impact on neuromuscular synaptic function and, consequently, on muscle strength, ultimately affecting the lifespan of animals. Inhibition of autophagy also exacerbates aging phenotypes in muscle, such as mitochondrial dysfunction, oxidative stress, and profound weakness. Mitochondrial dysfunction and oxidative stress directly affect acto-myosin interaction and force generation but show a limited effect on stability of neuromuscular synapses. These results demonstrate that age-related deterioration of synaptic structure and function is exacerbated by defective autophagy. © 2014 The Authors.

Gava P.,University of Padua | Kern H.,Ludwig Boltzmann Institute of Electrical Stimulation and Physical Rehabilitation | Carraro U.,Fondazione Ospedale San Camillo
Experimental Aging Research | Year: 2015

Background/Study Context: The capacity to perform everyday tasks is directly related to the muscular power the body can develop (see Appendix). The age-related loss of power is a fact, but the characterization or the rate of muscle power loss remains an open issue. Data useful to study the decline of the skeletal muscles power are largely available from sources other than medical tests, e.g., from track and field competitions of Masters athletes. The aim of our study is to identify the age-related decline trend of the power developed by the athletes in carrying out the track and field events.Methods: Absolute male world records of 16 events were collected along with world records of male Masters categories. Performance was normalized with respect to the absolute record; the performance of various age groups is consequently represented by a number ranging from 1 (world absolute records) to 0 (null performance). The performance of a jumping event is transformed into a parameter proportional to the power developed by the athletes: the displacement of the center of gravity of the athlete. Throwing events are further normalized for the decreasing weight of the implements with the increasing age of the Masters athletes.Results: Most track and field events show a linear decline to 70 years. The annual rate of power decline for all the events (running, throwing, and jumping), using a simplified synthesis, is 1.25% per year. The events that involve mostly upper limbs (shot put, javelin throw) show a higher rate of decline (1.4% per year) compared to those where the lower limbs are mostly involved (long jump 1.1%, track events 0.6-0.7% per year). This analysis of muscle power decline is only partially in line with the results of works based on clinical tests. A clarification of the reasons for such discrepancy may provide clinically significant information.Conclusion: Human power decline in Masters athletes was analyzed, adopting a coherent approach based on an extended database. Skeletal muscle power starts declining after the age of 30, with slight variations depending on the events. This conclusion is in line with only some of the previous studies. The various trend lines point to 0 at the age of 110 years, which is in line with the present human survival age. The study can be further developed with a suitable database for male and female Masters performances to facilitate longitudinal studies, which are currently lacking. © 2015 Taylor and Francis Group, LLC.

Hofstoetter U.S.,Medical University of Vienna | McKay W.B.,Spinal USA | Tansey K.E.,Spinal USA | Tansey K.E.,Emory University | And 3 more authors.
Journal of Spinal Cord Medicine | Year: 2014

Context/objective: To examine the effects of transcutaneous spinal cord stimulation (tSCS) on lower-limb spasticity. Design: Interventional pilot study to produce preliminary data. Setting: Department of Physical Medicine and Rehabilitation, Wilhelminenspital, Vienna, Austria. Participants: Three subjects with chronic motor-incomplete spinal cord injury (SCI) who could walk ≥10 m. Interventions: Two interconnected stimulating skin electrodes (Ø 5 cm) were placed paraspinally at the T11/T12 vertebral levels, and two rectangular electrodes (8 × 13 cm) on the abdomen for the reference. Biphasic 2 mswidth pulses were delivered at 50 Hz for 30 minutes at intensities producing paraesthesias but no motor responses in the lower limbs. Outcome measures: The Wartenberg pendulum test and neurological recordings of surface-electromyography (EMG) were used to assess effects on exaggerated reflex excitability. Non-functional co-activation during volitional movement was evaluated. The timed 10-m walk test provided measures of clinical function. Results: The index of spasticity derived from the pendulum test changed from 0.8 ± 0.4 pre- to 0.9 ± 0.3 poststimulation, with an improvement in the subject with the lowest pre-stimulation index. Exaggerated reflex responsiveness was decreased after tSCS across all subjects, with the most profound effect on passive lower-limb movement (pre- to post-tSCS EMG ratio: 0.2 ± 0.1), as was non-functional co-activation during voluntary movement. Gait speed values increased in two subjects by 39%. Conclusion: These preliminary results suggest that tSCS, similar to epidurally delivered stimulation, may be used for spasticity control, without negatively impacting residual motor control in incomplete SCI. Further study in a larger population is warranted. © The Academy of Spinal Cord Injury Professionals, Inc. 2014.

Hofstoetter U.S.,Medical University of Vienna | Krenn M.,Medical University of Vienna | Danner S.M.,Medical University of Vienna | Danner S.M.,Vienna University of Technology | And 7 more authors.
Artificial Organs | Year: 2015

The level of sustainable excitability within lumbar spinal cord circuitries is one of the factors determining the functional outcome of locomotor therapy after motor-incomplete spinal cord injury. Here, we present initial data using noninvasive transcutaneous lumbar spinal cord stimulation (tSCS) to modulate this central state of excitability during voluntary treadmill stepping in three motor-incomplete spinal cord-injured individuals. Stimulation was applied at 30Hz with an intensity that generated tingling sensations in the lower limb dermatomes, yet without producing muscle reflex activity. This stimulation changed muscle activation, gait kinematics, and the amount of manual assistance required from the therapists to maintain stepping with some interindividual differences. The effect on motor outputs during treadmill-stepping was essentially augmentative and step-phase dependent despite the invariant tonic stimulation. The most consistent modification was found in the gait kinematics, with the hip flexion during swing increased by 11.3°±5.6° across all subjects. This preliminary work suggests that tSCS provides for a background increase in activation of the lumbar spinal locomotor circuitry that has partially lost its descending drive. Voluntary inputs and step-related feedback build upon the stimulation-induced increased state of excitability in the generation of locomotor activity. Thus, tSCS essentially works as an electrical neuroprosthesis augmenting remaining motor control. © 2015 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

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