Muscle Bio Exam #4

Limb Girdle Muscular Dystrophy (LGMD)

describes a group of inherited diseases resulting from mutations in gene encoding proteins involved in maintaining skeletal muscle membrane stability

disease onset (2nd or 3rd decade)

Limb Girdle Muscular Dystrophy (LGMD) varies in time of…

Big muscles in hip and shoulder

For Limb Girdle Muscular Dystrophy (LGMD), ________ are affected first

milder; slower

LGMD has generally ____ and _____ progression than DMD

8; 15

LGMD can be divided into ____ autosomal dominant forms and ____ autosomal recessive forms

caveolinopathy

Caveolin Deficiency (LGMD1C) is known as…

autosomal dominant

caveolinopathy is an _______ for of LGMD; is very rare; and has a normal range of life expectancy

very distal form of myopathy (doesn’t affect the “things that matter” as much, such as heart and respiratory muscles)

why is caveolinopathy (LGMD1C) not as problematic of other forms of LGMD?

Myostatin

______ Inhibition Reverses Muscle Atrophy

mutant Cav and mutant MSTN

double Tg is __________ and is very similar to wild type

• LGMD2B

• Myoshi myopathy (MM)

• Distal anterior compartment myopathy

Mutation in gene Dysferlinopathy (LGMD2B) gives rise to these 3 forms of muscular dystrophy

skeletal

Although dysferlin is expressed widely, its mutation affects only _____ muscle phenotype

muscle cell membrane repair

dysferlin plays an essential role in…

• Sudden onset: late teens or early 20s

• Inability to tiptoe

• Calf pain and swelling

• Good prior muscular prowess

• Very high serum CK

• Inflammation prominent (mostly T cells and macrophages)

• Greatly reduces membrane repair efficiency of cardiac muscle

phenotype of Dysferlinopathy (LGMD2B)

Dysferlinopathy (LGMD2B)

diamond on quadriceps is a phenotypical sign of…

Sarcoglycanopathies (LGMD2C-F)

Collective name for a genetically and phenotypically heterogeneous group of muscular dystrophies caused by mutation of any of the four genes alpha, beta, gamma, delta; Severe childhood-onset autosomal recessive muscular dystrophy(SCARMD), Normal dystrophin levels but other DGC proteins are compromised

alpha-sarcoglycanopathy

First to be discovered and Most frequent form of Sarcoglycanopathies; Onset 8-10 months; Difficulties running and climbing stairs; Weak pelvic area muscles. Proximal muscles show marked atrophy while calf muscles are hypertrophic; Weakness in the scapular muscles; Trunk muscles affected and neck muscles spared; Advanced stage marked by muscle contracture; Cardiac function normal

CK; variation

alpha-sarcoglycanopathy has elevated levels of serum ___, and muscle biopsies show _____ in muscle fiver size

Myotonic Dystrophy

Inherited disorder of the muscles and other body systems; Most common form of muscular dystrophy that begins in adulthood

progressive muscle wasting and weakness, particularly in the lower legs, hands, neck, and face; Other defects may include cataract, cardiac conduction defect, infertility

Myotonic Dystrophy is characterized by…

second, third

phenotype for myotonic dystrophy usually occurs in the _____ or _____ decade

severity

______ varies widely among people with MMD/MD

Type I

there are two types of MMD/MD, is type I or type II more severe? (two types are caused by mutations in 2 different genes)

40,000

About ______ people in US have MD

dystrophia myotonica-protein kinase (DM-PK) gene (or CNBP for Type II)

MD is caused by a defect in…

triplet (CTG) repeats [severity varies with number of repeats]

MD is caused by _______ in the 3’ un-translated region of the gene (3’UTR)

• Muscle weakness

• Abnormal EMGs

• Balding in the prefrontal area

• Cataract

• Genetic testing to look for CTG repeat

diagnosis of MD is based on…

Treating the manifestation of the disease:

• Wheelchair

• Orthotics

• ECG to monitor heart performance

• Pacemaker when necessary

• Pain management

• Hormone replacement for hyopgonadism

• Cataract surgery if necessary

• Genetic counseling

Treatment of MD

Emery-Dreifuss Muscular Dystrophy (EMD)

Due to a defect in either Emerin or Lamin A/C (nuclear membrane); Most common cause is defective emerin protein (1 in 100,000)

Can be inherited in X-linked (X-EDMD) autosomal recessive (Emerin) or Autosomal dominant form (AD-EDMD) as a result of defect in LMNA gene

• Slowly progressive muscle weakness and wasting in shoulders/upper chest/back

• Muscle contracture present

• Onset in teen years

• Heart problems may cause sudden death

• Major cause of mortality and morbidity in EDMD is cardiac disease, which is consistently present

EMD phenotype

Facioscapulohumeral muscular dystrophy (FSHD)

third most common muscular dystrophy after DMD and MD; First described in 1886 as Landouzy Dejerine; Prevalence is 1:20,000

• Usually adult onset - Age 20 for men; Age 30 for women'; Only 5% children

• Progresses very slowly

• Facial muscle weakness - Eyelids, Whistling, Pronunciation

• Shoulder weakness

• Weakening of arm muscles - Do not respond to exercise

Phenotype of Facioscapulohumeral muscular dystrophy (FSHD)

autosomal dominant; D4Z4; 4

cause of Facioscapulohumeral muscular dystrophy (FSHD) - _________ inheritance; due to deletion of ____ repeat of chromosome ___

DUX4 (DUX4 usually silent due to tight heterochromatin packing; As a result of deletion, the DNA is less tightly packed and DUX4 is more available for transcription)

Usually have 11-150 repeats of D4Z4; Less than 11 as well as overexpression of _____ leads to FSHD – toxic gain of function

transcriptional activator; zygotic genome activation; embryo genesis

DUX4 acts as a _________, likely stimulating ________ during early __________. Its expression is normally restricted to cleavage stage embryos, testes, and thymus, and it is silenced in most adult somatic tissues

toxic gain of function

Misexpression of DUX4 triggers a _________, causing apoptosis, oxidative stress, and chronic inflammation in muscle cells, which results in muscle weakness and atrophy over time

no

Are there any drugs to treat FSHD?

• Accumulation of genetic damage or mutations in genes, chromosomes, and mitochondria

• Loss of immune functions and autoimmunity

• Accumulation of insoluble aggregates

• Abnormal modification of proteins

• Damage by reactive oxygen species (ROS)

• Hormone imbalance and a decline in homeostasis

causes of aging

Sarcopenia

Involuntary loss of lean muscle mass as a result of ageing; Often associated with increase in fat

10-24; 30

_____% in 65-70 year olds and over ____% muscle loss in those over 80

growth hormone; IGF-1; sex hormone; cytokine production

sarcopenia causes a decrease in _____, _____, and ______, and increased _______

chronic malnutrition, sedentary life style, and smoking

sarcopenia is enhanced by…

25-50

Ageing process is associated with a _____% reduction of the a-motoneurons (a-MN). Small MN, which are more preserved than large a-MN, continue to innervate type I fibers

IGF-1

overexpression of ______ prevents type IIb myosin loss in mice due to aging

64; 28

Testosterone levels decrease by ___% in males between the age of 25 and 85; In females there is ___% decline in the levels of bio-available testosterone between ages 25 and 85

women

Decline in bio-available testosterone is not linked to decreased muscle mass and strength in _______

cross sectional area; cell number and myogenesis; cancer

Testosterone dosing increases __________ of type I and II fibers; Testosterone promotes muscle growth by increasing _________; Giving Tstne as a supplement increases risk of ________

Cachexia

Complex condition that involves weight loss, lipolysis, loss of muscle, and some visceral protein, anorexia, chronic nausea, and weakness

• Some autoimmune disorders

• Addiction to certain drugs

• Chronic obstructive pulmonary disease

• Congestive heart failure

• Cancer

• AIDS

• Tuberculosis

common causes of Cachexia

you lose both at the same time (which is not typical, usually when losing weight you should lose fat first and then muscle)

In cachexia, do you lose muscle or fat first?

spindle, striated

smooth muscle is ____ shaped and is not ____

parallel, series

smooth muscle forces add in _____, not in _____

actin

Smooth muscle has higher ratio of _____ filaments

directional

smooth muscle has greater _____ freedom

6:1; 15:1

Actin:Myosin for smooth is ____ while it is ____ for striated

We don’t know!

How is force of smooth muscle maintained even after signal turns off?

neurotransmitters, hormones, drugs, stretch

Ca Entry into Smooth Muscle can be caused by…

• Vascular

• Respiratory

• Urinary

• Reproductive

• Gastrointestinal

• Ocular

common places where there are smooth muscle disorders

75

Premature births account for ___% of all neonatal death

12

___% of US births are premature

50

In ___% of cases, the cause of premature births is never determined

quiescent phase

As myometrium stretches, leads to increased chance of contractility, yet it doesn’t occur; This “uncoupling” is known as ________

CAP

Upregulation of endogenous inhibitors causes “coupling” again; ____ proteins signal “coupling”

Caldesmon; ERK activation; Caldesmon phosphorylation at ERK sites

______ increases during pregnancy; ______ increases during labor; ___________ increases during labor

ERK

____ Inhibitor Delays Onset of Labor

cardiovascular disease (CVD)

leading cause of death in the world

Age, gender, hypertension, cholesterol, smoking, alcohol, family history, metabolic syndrome (obesity, diabetes), physical inactivity, aortic stiffness

risk factors to cardiovascular events

Aortic stiffening

________ transmits increased pulse pressure to more fragile peripheral vessels.

ECM, calcification

what contributes to aortic stiffness?

focal adhesions

smooth muscle stiffness can be regulated via…

formation; maintenance; repair

Myogenesis is fundamental to the ______, ______ and _____ of skeletal muscle and associated tissues

myoblasts; multinucleated myofibers

Skeletal muscle development requires the formation of ______ that can fuse with each other to form ______________

birth

Distinct primary, secondary, slow, fast myofibers are formed by the time of _____; These fibers arise at distinct stages of development: embryonic, fetal and perinatal

build, break down, mature

blast (_____), clast (_____), cyte (____)

myocytes, myofibers

Myoblasts receive a cue to develop into ______ which aggregate into ______

KNOW THIS IMAGE FOR EXAM!!!

ectoderm; mesoderm; endoderm

zygote blastula gastrula differentiates into ____, ____ and _____

ectoderm

develops/differentiates into epidermis and associated structures and the brain and nervous system

endoderm

develops/differentiates into inner lining of digestive tract, glands, and inner lining of respiratory tract

mesoderm

develops/differentiates into notochord, somites (further develops into muscle), and mensenchyme (further develops into heart and circulatory system)

segmented somites

The paraxial mesoderm will develop into…

muscle, dermis, cartilage, tendons, and the axial skeleton

Somites are transient embryonic structures that later give rise to…

segmented somites

The paraxial mesoderm will develop into…

somites

Limb and trunk muscle arise from the _____

non-somitic paraxial mesoderm

Head muscles arise from the _______________ that is with in the developing head region

back muscles (epaxial)

Dorsal –medial portion of the somite give rise to _________

Abdominal and body wall (hypaxial)

Ventral lateral portion of the somites give rise to _________

limb field; lateral lip of dermomyotome

At the limb level, the cells predetermined to form skeletal muscle migrate to the _______ from ________

head

Somites migrate from head down (rostral to caudal), thus maturing near _____ first

Basic Helix Loop Helix protein

Consist of 2 alpha-helices connected at a fixed angle by a short stretch of polypeptide chain (the “turn”)

E-box; major

Basic Helix Loop Helix protein- Recognition helix recognizes and bind to specific DNA sequences (____) by forming H-bonds with bases located in the _____ groove

hydrophobic; recognition

Basic Helix Loop Helix protein- Second helix stabilizes the overall configuration through _______ interactions with the _______ helix; Generally dimeric

Muscle Regulatory factors (MRFs)

a family of basic helix-loop-helix (b HLH) transcription factors that regulate myogenesis

• MyoD

• Myf 5

• Myogenin

• MRF4

examples of Muscle Regulatory factors (MRFs)

differentiated skeletal muscle cells

Muscle Regulatory factors (MRFs), when over expressed in fibroblasts, converts the cells to ______________ that transcriptionally activate expression of muscle-specific genes such as myosin and actin

MyoD; Myf5

_____ and _____ are the earliest markers of myogenic cells. However, they are expressed in specific spatio-temporal fashion at earlier stage but later they overlap

epaxial; hypaxial

Myf5 is expressed in the cells that will give rise to _____ muscles and MyoD is expressed in cells that give rise to _____ muscles, although at a later point than Myf5

there is no muscle development, will lead to embryonic death

if you double knock out MyoD and Myf5…

Myogenin

______ is required for late but not early aspects of myogenesis during mouse development

severe skeletal muscle reduction (Myoblasts form and proliferate, but never differentiate into myocytes)

knocking out myogenin leads to…