Sarcopenia and Muscular Dystrophies Lecture Notes PDF

Sarcopenia and Muscular dystrophies Dr. Frederic von Wegner WARNING  This material has been reproduced and communicated to you by...

Sarcopenia and Muscular dystrophies Dr. Frederic von Wegner WARNING  This material has been reproduced and communicated to you by or on behalf of the University of New South Wales in accordance with section 113P of the Copyright Act 1968 (Act).  The material in this communication may be subject to copyright under the Act. Any further reproduction or communication of this material by you may be the subject of copyright protection under the Act.  Do not remove this notice Learning objectives - give a definition of sarcopenia - discuss the relationship between risk factors and pathomechanisms in sarcopenia - name some laboratory and clinical findings in sarcopenia - which treatment strategies for sarcopenia exist - describe the clinical course of Duchenne muscular dystrophy (DMD) - what is the cause, what are the pathomechanisms of DMD? - explain the relationship between cell mechanics and excitability in DMD - discuss the relationship between physical exercise and DMD Sarcopenia - sarx (gr.) = flesh, sarco- = muscle (endoplasmic ret. => sarcoplasmic ret., plasmalemma => sarcolemma,...) - penia = lack of (leukopenia, …) - concept over time: low muscle mass → low muscle strength → earlier diagnosis, better predictor of adverse outcome - sarcopenia is a muscle disease (muscle failure), not normal ageing - not only muscle quantity, also muscle quality - a progressive disease Cruz-Jentoft 2019 Grip strength and age colours: birth cohorts percentiles: 10, 25, 50, 75, 90 statistical cut-off threshold for force loss screening Cruz-Jentoft 2019 Sarcopenia Public health relevance: - prevalence: depends on method: (1-30% community, >10% in acute hospital care and long-term care) - increased risk of falls and fractures - limits daily living activities => loss of independece, quality of life ↓ - mobility disorders - associations / correlations with: cardiac + respiratory problems, cognitive deficits - health costs ↑ (hospitalisation) - when hospitalized, sarcopenia patients generate more costs (x 2), old+young! Woo 2017 Cruz-Jentoft 2019 Sarcopenia: SARC-F screening tool - evaluated in 3 large populations - sensitivity: low to moderate - specificity: very high => severe cases reliably detected mild cases can escape Woo 2017 Sarcopenia – objective criteria - muscle strength: grip strength, handheld dynamometer, chair stand test - muscle quantity: magnetic resonance imaging, computer tomography - X-ray absorptiometry (DXA) - bioelectric impedance analysis (BIA), portable - physical performance: gait speed, + balance test, +chair stand test, 400 m walk rd test - lumbar 3 vertebra imaging (CT) – correlates with whole-body muscle - mid-thigh muscle measurement (MRI, CT) - muscle quality measurement (high-sensitivity MRI for example) measures e.g. fat infiltration - muscle ultrasound imaging - serum biomarkers (under evaluation): inflammation, metabolism,... Cruz-Jentoft 2019 Sarcopenia – subtypes - forms: primary (age-related) and secondary (inflammatory, cancer, inactivity, nutrition) - time course: acute ( type I/II ratio increases with age => loosely packed fibres in aged subj. (connective tissue) Lexell, 1988 Ageing atrophy: some correlations decreasing muscle area 60% type I: 40% type I: decreasing muscle fibre N Lexell, 1988 Sarcopenia - management - non-pharmacologic: - resistance and strength training both effective in prevention and treatment, affect protein synthesis/degradation balance Sarcopenia - management - non-pharmacologic: - resistance and strength training both effective in prevention and treatment, affect protein synthesis/degradation balance - pharmacological: - not approved: DHEA (Androsterone-like > metabolism), GH (growth hormone) increases muscle mass, but not strength/function IGF (insuline-like growth factor) testosterone: increases muscle mass and strength, but: risk↑ for: prostate cancer, virilization, cardiovasc. events - under investigation: vitamin D, myostatin,... Sarcopenia - management - non-pharmacologic: - resistance and strength training both effective in prevention and treatment, affect protein synthesis/degradation balance - pharmacological: - not approved: DHEA (Androsterone-like > metabolism), GH (growth hormone) increases muscle mass, but not strength/function IGF (insuline-like growth factor) testosterone: increases muscle mass and strength, but: risk↑ for: prostate cancer, virilization, cardiovasc. events - under investigation: vitamin D, myostatin,... - nutrition: - curcuma, ginger, grape seed (and more) ? - malnutrition in elderly Sarcopenia: physical activity works - ‘common sense’ recommendation seems to work: physical activity prevents sarcopenia - different types of PA similar effects Steffl, 2017 Sarcopenia Cruz-Jentoft 2019  Muscular dystrophies Hereditary and progressive diseases that lead to: - muscle necrosis (cell death) - and replacement of muscle by connective and fat tissue Muscular dystrophies Example dystrophies associated with sarcolemmal proteins and enzymes e.g.: LGMD: limb girdle muscular dystrophy → proximal muscles shoulder, hip DMD: Duchenne BMD: Becker Amato, Neuromuscular Disorders Muscular dystrophies Examples of dystrophies associated with sarcomeric and nuclear proteins LGMD – limb girdle muscular dystrophy → proximal muscles shoulder, hip MEB: muscle, eye, brain OPMD: oculo-pharyngeal (...) Amato, Neuromuscular Disorders Muscular dystrophies… too many ??? Amato, Neuromuscular Disorders Duchenne muscular dystrophy  X-chromosomal recessive disease  1/3 of cases spontaneous mutations  incidence: 1/3500 (male births) = ↑  initially normal development  2-6 yrs: ‘waddling’ gait, Gower’s sign https://en.wikipedia.org/wiki/X-linked_recessive_inheritance Duchenne muscular dystrophy  X-chromosomal recessive disease  1/3 of cases spontaneous mutations  incidence: 1/3500 (male births) = ↑  initially normal development  2-6 yrs: ‘waddling’ gait, Gower’s sign https://en.wikipedia.org/wiki/X-linked_recessive_inheritance Duchenne muscular dystrophy (DMD)  X-chromosomal recessive disease  1/3 of cases spontaneous mutations  incidence: 1/3500 (male births) = ↑  initially normal development  2-6 yrs: ‘waddling’ gait, Gower’s sign  problems with running  calf pseudohypertrophy  = fatty degeneration  generalization over years,  cardiac muscle affected  early death from respiratory  complications (< 30 y) https://en.wikipedia.org/wiki/X-linked_recessive_inheritance DMD pathology: dystrophin - giant 427 kDa protein - actinin/spectrin family - structural protein, N-terminus binds actin - binds many other structural proteins, e.g.: - dystroglycan - syntrophin - mutations → short, unstable and dysfunctional variants Muntoni, Lancet Neurol, 2003 DMD pathology: dystrophin healthy - giant 427 kDa protein - actinin/spectrin family - structural protein, N-terminus binds actin - binds many other structural proteins, e.g.: - dystroglycan - syntrophin - mutations → short, unstable and dysfunctional variants DMD dystrophin antibody staining Muntoni, Lancet Neurol, 2003 Amato, Neuromuscular Disorders Muntoni, Lancet Neurol, 2003 DMD cellular changes Amato, Neuromuscular Disorders Becker muscular dystrophy - ‘short dystrophin’ atrophy fat intrusion Amato, Neuromuscular Disorders DMD and excitability changes: Ca2+ currents mdx mouse model Friedrich, PLoS One, 2008 DMD and excitability changes: Ca2+ currents model of dystrophin-DHPR interaction (mouse) gene therapy Friedrich, PLoS One, 2008 Structural defects and cell mechanics - advanced structural microscopy shows: - disruptions of myofibrils - split fibres (progressive) - what does that mean for contractions? - what does that mean for physical therapy and exercise recommendations in DMD? Friedrich, Biophys J, 2010 Pathological cell mechanics 20 µm cell instability → damage → pathological shear forces → damage - cell damage: → uncontrolled Ca2+ influx → apoptosis (programmed cell death) Friedrich, Biophys J, 2010 DMD and exercise Kostek, Exerc Sports Sci Rev, 2017 DMD and exercise - in animals: - voluntary wheel running: positive effects on force, fatigue resistance in mdx limb muscles, controversial results in diaphragm, cardiac: all effects (↑↓) found (negative: dilation, wall thinning, ejection fraction ↓) - swimming: beneficial for most limb muscles, more strength, shorter relaxation time (= improved Ca2+ handling), less fatigue cardiac and respiratory muscles: more fibrosis, more inflammation - forced running: increased muscle damage, impaired function, plasma-CK ↑ progressive loss of force, extremely bad: downhill running (eccentric contr.) Spaulding, Med Sci Sports Exerc, 2018 DMD and exercise - in animals: - voluntary wheel running: positive effects on force, fatigue resistance in mdx limb muscles, controversial results in diaphragm, cardiac: all effects (↑↓) found (negative: dilation, wall thinning, ejection fraction ↓) - swimming: beneficial for most limb muscles, more strength, shorter relaxation time (= improved Ca2+ handling), less fatigue cardiac and respiratory muscles: more fibrosis, more inflammation - forced running: increased muscle damage, impaired function, plasma-CK ↑ progressive loss of force, extremely bad: downhill running (eccentric contr.) - in humans: - mostly respiratory muscle training => increased resp. endurance, pressure, vital capacity - limb muscles: unknown risk, ethical problem, few studies, muscle probably able to adapt to training, but unknown effects on cardiac + respiratory function Spaulding, Med Sci Sports Exerc, 2018  DMD summary 1. DMD is a lethal, frequent hereditary disease of skeletal and cardiac muscle affecting children and young adult men 2. the cause is a lack of the giant structural protein dystrophin 3. dystrophin links many proteins providing membrane and cellular stability 4. dystrophin pathology is associated with changes in excitability 5. pathological cell mechanics can accelerate cell damage and cell death 6. the optimum amount and type of exercise is still unknown Thank you!