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Carraro 2012 Abstract Bioblast

From Bioblast
Carraro U (2012) Muscle training in ageing, denervation and beyond. Mitochondr Physiol Network 17.12.

Link: MiPNet17.12 Bioblast 2012 - Open Access

Carraro U, Zampieri S, Kern H (2012)

Event: Bioblast 2012

Ugo Carraro

During the last decade we contributed to research on rehabilitation of aging complications studying mechanisms and effects of physical exercise induced by Functional Electrical Stimulation (FES) in the special case of Spinal Cord Injury patients affected by complete injury of the Conus Cauda, a syndrome where the denervated leg muscles are fully disconnected from the nervous system. Denervated human muscles become unexcitable with commercial electrical stimulators and undergo ultra structural disorganization within a few months from SCI, while severe atrophy with nuclear clumping (Figure 1) and fibro-fatty degeneration appear within 3 and 6 years, respectively [1-4]. To counteract these progressive changes a novel therapy concept for paraplegic patients with complete lower motor neuron denervation of the lower extremity was developed in Vienna: home-based functional electrical stimulation of long-term denervated muscles (h-b FES). New electrodes and a safe stimulator for h-b FES have been designed to reverse severe atrophy by delivering high-intensity (up to 2,4 J) and long-duration impulses (up to 150 ms) able to elicit contractions of denervated skeletal muscle fibers in absence of nerves [5,6]. At the same time, specific clinical assessments and training strategies were developed at the Wilhelminenspital Wien, Austria [7], based on sound evidence from animal experiments [8]. Main results [9-11] of a clinical study on patients which completed the 2-year h-b FES training are: 1. significant increase of muscle mass and of myofiber size, with striking improvements of the ultra-structural organization; 2. recovery of tetanic contractility with significant increase in muscle force output during electrical stimulation; 3. capacity to perform FES-assisted stand-up and stepping-in-place exercise (Figure 2). The study demonstrated that h-b FES of permanent denervated muscle is an effective home therapy that results in rescue of muscle mass, function and perfusion Additional benefits, important for the patients, are the improved cosmetic appearance of the legs and the enhanced cushioning effect for seating.

Continued in free text.

Keywords: Muscle, myopathy, ageing, denervation, SCI, oncology, rehabilitation, home-based FES

Labels: Pathology: Aging;senescence 

Organism: Human  Tissue;cell: Skeletal muscle 

Affiliations and author contributions

Ugo Carraro (1), Sandra Zampieri (1,2), Helmut Kern (2)

(1) Laboratory of Translational Myology, Dept. Biomedical Sciences, University of Padua, Italy; (2) Ludwig Boltzmann Institute of Electrical Stimulation and Physical Rehabilitation, Dept. Physical Medicine and Rehabilitation, Wilhelminenspital Wien, Austria


Abstract continued

We are now extending our studies to application of h-b FES to the larger cohort of elderly. In order to assess the effects of exercise on aging rehabilitation, we are analyzing by morphometric light and electron microscopy and molecular biology quadriceps muscle biopsies from young (23 years) [12] and senior male subjects: sedentary elderly and senior sportsmen (a peculiar group of subjects that performed life-long sport activities) with a mean age of 70 years. The group of sedentary seniors was also exercised for 10 weeks with two different types of training (leg press or electrical stimulation) and the analyses performed before and after the training period. Preliminary results confirm the effectiveness of h-b FES.

Based on our recent observation of the presence of a subclinical myopathy in patients affected with newly diagnosed colorectal cancer [13], we are now extending our approaches to oncologic rehabilitation. The factors associated with a subclinical myopathy at this stage of disease are unknown. A comprehensive study on the potential molecular mechanisms that are responsible for this cancer-associated myopathy could possibly provide new diagnostic and prognostic markers and new therapeutic targets to prevent the severe loss of muscle tissue which characterizes late-onset cancer cachexia.


  1. Rossini K, Zanin ME, Carraro U (2002) To stage and quantify regenerative myogenesis in human long-term permanent denervated muscle. Basic Appl Myol 12: 277–286.
  2. Kern H, Boncompagni S, Rossini K, Mayr W, Fanò G, Zanin ME, Podhorska-Okolow M, Protasi F, Carraro U (2004) Long-term denervation in humans causes degeneration of both contractile and excitation-contraction coupling apparatus that can be reversed by functional electrical stimulation (FES). A role for myofiber regeneration? J Neuropath Exp Neurol 63: 919–931.
  3. Boncompagni S, Kern H, Rossini K, Hofer C, Mayr W, Carraro U, Protasi F (2007) Structural differentiation of skeletal muscle fibers in the absence of innervation in humans. Proc Natl Acad Sci U S A 104: 19339–19344.
  4. Kern H, Carraro U, Biral D, Adami N, Zampieri S (2009) Severely atrophic muscle fibers with nuclear clumps survive many years in permanently denervated human muscle. The Open Pathol J 3: 106-110.
  5. Mayr W, Bijak M, Rafolt D, Sauermann S, Unger E, Lanmüller H (2001) Basic design and construction of the Vienna FES implants: existing solutions and prospects for new generations of implants. Med Eng Phys 23: 53–60.
  6. Hofer C, Mayr W, Stöhr H, Unger E, Kern H (2002) A stimulator for functional activation of denervated muscles. Artif Organs 26: 276–279.
  7. Kern H, Hofer C, Mayr W, Carraro U (2009) European Project RISE: Partners, protocols, demography. Basic Appl Myol/ Europ J Translat Myol 19: 211-216.
  8. Squecco R, Carraro U, Kern H, Pond A, Adami N, Biral D, Vindigni V, Boncompagni S, Pietrangelo T, Bosco G, Fanò G, Marini M, Abruzzo PM, Germinario E, Danieli-Betto D, Protasi F, Francini F, Zampieri S (2009) Despite lost contractility, a sub-population of rat muscle fibers maintains an assessable excitation-contraction coupling mechanism after long-standing denervation. J Neuropath Exp Neurol 68: 1256-1268.
  9. Kern H, Carraro U, Adami N, Hofer C, Loefler S, Vogelauer M, Mayr W, Rupp R, Zampieri S (2010) One year of home-based Functional Electrical Stimulation (FES) in complete lower motor neuron paraplegia: Recovery of tetanic contractility drives the structural improvements of denervated muscle. Neurol Res 32: 5-12.
  10. Kern H, Carraro U, Adami N, Biral D Hofer C, Forstner C, Mödlin M, Vogelauer M, Boncompagni S, Paolini C, Mayr W, Protasi F, Zampieri S (2010) Home-based Functional Electrical Stimulation (h-b FES) recovers permanently denervated muscles in paraplegic patients with complete lower motor neuron lesion. Neurorehab Neur Rep 24: 709-721.
  11. Gargiulo P, Reynisson PJ, Helgason B, Kern H, Mayr W, Ingvarsson P, Helgason T, Carraro U (2011) Muscle, tendons, and bone: structural changes during denervation and FES treatment. Neurol Res 33: 750-758.
  12. Kern H, Pelosi L, Coletto L, Musarò A, Sandri M, Vogelauer M, Trimmel L, Cvecka J, Hamar D, Kovarik J, Löfler S, Sarabon N, Protasi F, Adami N, Biral D, Zampieri S, Carraro U (2011) Atrophy/hypertrophy cell signaling in muscles of young athletes trained with vibrational-proprioceptive stimulation. Neurol Res 33: 998-1009.
  13. Zampieri S, Valente M, Adami N, Biral D, Ghirardello A, Rampudda ME, Vecchiato M, Sarzo G, Corbianco S, Kern H, Carraro U, Bassetto F, Merigliano S, Doria A (2010) Polymyositis, dermatomyositis and malignancy: a further intriguing link. Autoimmun Rev 9: 449-453.

Figure 1

Denervated human muscle

Four-year denervated human muscle showing severely atrophic myofibers in which contractile apparatus is almost absent, but nuclear clumps are frequent (left panel). Clumps of nuclei are better identified in transvers sections (right panel).

Figure 2

Stand-up exercise

Stand-up exercise by h-b FES. Note that the blue large electrodes fully cover the thigh muscles.