Sparing dystrophic muscle

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Jeffry Hodge
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1 Sparing dystrophic muscle

2 Research at NMDRC Skeletal muscle Development and Hypertrophy Dystrophic Pathology Skeletal Muscle Regeneration Stem cells and Cell Transplantation Identification and manipulation of factors which play a role in hypertrophy Callipyge sheep Myostatin Growth Factors Delivery of factors to dystrophic skeletal muscle to ameliorate the progression of dystrophy Understanding and enhancing skeletal muscle regeneration Use of precursor cells as a gene correction methodology

3 The Central Dogma 3mG mrna Protein DNA

4 H3 H4 H2B H4 H2A H3 DNA Packaging

5 Reading the DNA code RNA DNA

6 A Simple Cell 3mG RNA Protein

9 Muscle Development and Regeneration Myoblast Myotube Fusion

10 FSHD

11 FSHD Majority of FSH cases linked to D4Z4 repeat on chromosome 4 General population repeats FSH 1 to 10 Small proportion (<5%) phenotypic

12 FSHD No mutation in a specific gene Must be other mechanisms that result in loss of control

14 Epigenetic mechanism Improper packaging of DNA leaves it open Altered production of genes H3 H4 H2B H4 H2A H3

16 Loss of control FRG1 = muscular dystrophy FRG2 or ANT1 = no effect

17 Experimental Approaches to Treatment

18 Cell transplantation from non-affected muscles Drugs that change methylation status

19 Principle of Cell Transplantation NORMAL MUSCLE makes dystrophin DYSTROPHIC MUSCLE lacks dystrophin Stuart Hodgetts Tracey Pullen-Lee

20 Principle of Myoblast Transfer Therapy Cultured normal myoblasts injected into dystrophic muscle MOSAIC MUSCLE FIBRE

21 Myotonic Dystrophy Unstable expansion of CTG repeats Accumulation of RNA in nucleus (cellular toxicity) Toxic gain of function

23 A Simple Cell 3mG RNA Protein

24 Muscle Development and Regeneration Myoblast Myotube Fusion

25 Therapeutic strategies Manipulation of RNA degradation pathways to clear accumulated RNA Flavonoids and DHEA-S alleviate toxic effects in tissue culture

26 Limb Girdle Type2A Calpain

28 LGMD 2A Calpain 3 Affected protein is an enzyme not a structural element? Reduced capacity for normal protein turnover Assumes a role in generalized protein clearance

29 Other roles for calpain 3 Cytoskeleton rearrangements Sarcomere formation and remodelling Cell death

31 Increasing muscle regeneration/growth Callipyge and myostatin

32 Research at NMDRC Skeletal muscle Development and Hypertrophy Dystrophic Pathology Skeletal Muscle Regeneration Stem cells and Cell Transplantation Identification and manipulation of factors which play a role in hypertrophy Callipyge sheep Myostatin Growth Factors Delivery of factors to dystrophic skeletal muscle to ameliorate the progression of dystrophy Understanding and enhancing skeletal muscle regeneration Use of precursor cells as a gene correction methodology

COCKETT, PhD Professor Utah State University ADVS Department 4815 Old Main Hill

33 Callipyge 1983 Solid Gold Hypertrophy of hindquarters SNP on Chromosome 18 (CLPG) beautiful buttocks Superior feed efficiency Polar overdominance NOELLE E. COCKETT, PhD Professor Utah State University ADVS Department 4815 Old Main Hill Logan UT tel. (435) fax. (435)

35 Solid Gold The Founder of Callipyge

36 Callipyge (CN) Normal (NN) Unaffected Affected

38 Target HDAC9

39 Effect of Valproate (VPA) A B C Control 5mM VPA 10mM VPA

40 Texel The Texel Breed is famed for its exceptional carcass qualities, which has resulted in the Breed becoming the dominant terminal sire used in the UK. QTL recently identified in region of myostatin gene. J Animal Sci. Nov 2004.

41 Myostatin

42 Vaccination against Myostatin Negative regulator of muscle cell growth Thus Need to remove (similar to MYO29)

43 Research at NMDRC Skeletal muscle Development and Hypertrophy Dystrophic Pathology Skeletal Muscle Regeneration Stem cells and Cell Transplantation Identification and manipulation of factors which play a role in hypertrophy Callipyge sheep Myostatin Growth Factors Delivery of factors to dystrophic skeletal muscle to ameliorate the progression of dystrophy Understanding and enhancing skeletal muscle regeneration Use of precursor cells as a gene correction methodology

Laboratoires Dom AVMM (Suisse) Inc. New Innovation in Peptide Therapy for Slimming

Laboratoires Dom AVMM (Suisse) Inc New Innovation in Peptide Therapy for Slimming Globally, Fat Facts 1 billion overweight adults 300 million obese adults A major risk for chronic diseases: Type 2 diabetes