Table 1.
Results of previously published data from various means of myostatin inhibition in animal models.
| Species/Model | Compound | Muscle Morphology | Fiber-Type Specific Changes | Absolute Force/ Glycolytic |
Specific Force/Glycolytic | Absolute Force/ Oxidative |
Specific Force/Oxidative | Stress-Induced Force Drop | Histopathological Effect of Myostatin Inhibition | Reference |
|---|---|---|---|---|---|---|---|---|---|---|
| Antibodies Blocking Myostatin | ||||||||||
| Mouse/wild-type (BALB/c, C57BL/6) |
JA16, ATA-842, mRK35, YN41, muSRK-015P, GYM-mFc | Fiber CSA increased in EDL [67] and Gas Increased weight of Gas, TA, Quad and TB, plantaris, Sol [68] |
Increased IIB fiber CSA, no effect on overall composition [69] | Increased grip strength [68,70,71] | [67,68,69,70,71,72] | |||||
| Mouse/mdx, Mouse/Sgcd−/−, Sgcg−/− |
JA16 | EDL: Increased weight and single fiber area [73,74]. Increase in TA, Quad, Gas [75] |
EDL: increased force | EDL: No effect | No effect |
Sgcd−/−: No improvement in histopathology of TA, EDL, Gas and diaphragm albeit hydroxyproline reduced in TA. Fibrosis in diaphragm increased (Sgcd−/− [75]) and decreased (mdx [73]) |
[73,74,75] | |||
| Mouse/mdx | PF-354 | Increase in hindlimb muscle weight of 5 weeks treatment, no effect after 8 weeks. No effect/reduction in CSA |
Diaphragm: No effect | Diaphragm increased (young)/no effect (old) | No effect | Diaphragm: Increased fiber size in young animals, decreased fiber size in old animals | [76] | |||
| Mouse/mdx, TgCTA1D286G, Sod1G93A, A17, Rat/Sod1G93A Mouse/SmnΔ7 |
mRK35/RK35 muSRK-015P (in SmnΔ7) |
TA, Gas, Quad, EDL, diaphragm weight increased. Increased CSA in TA, EDL. No effect on weight or CSA in soleus [77] |
Quad: Increased proportion of IIB fibers [78] Increase in IIB fiber CSA, no effect in remaining fiber-types [79] |
TA, EDL: Increased force Plantarflexor group increased torque [79] |
TA, EDL: No effect effect on plantarflexor group [79] |
Gas: reduced atrophy, preserved fiber diameter. Diaphragm integrity preserved [80]. Reduced collagen I, III, IV deposits. No effect on intranuclear inclusion bodies [77,81]. Increased number of tubular aggregates [78]. |
[72,77,78,79,80,81] | |||
| Mouse/ CB17-SCID, C57BL/6, (Dexamethasone atrophy) |
REGN1033 | Increased weight in Gas and TA. Fiber area increased in Gas | No effect on fiber type composition | TA: Increased force | TA: No effect | [82] | ||||
| Monkey/cynomolgus | MYO-029, Domagrozu-mab, GYM-cyfc |
Increased muscular circumference | [71,72,83] | |||||||
| Myostatin Propeptide Administration or Overexpression | ||||||||||
| Mouse/mdx | Recombinant propeptide-Fc | EDL: weight, CSA, single fiber area increased | EDL: Increased force | EDL: Increased force | No effect | Decreased pathological changes | [84] | |||
| Mouse/mdx | AAV8- MPRO76AFc |
TA, Quad, Gas, Diaphragm increased | TA: Increased force | TA: No effect | Larger fibers, less fibrosis | [85] | ||||
| Mouse/calpatin 3-null mice (LGMD2A), Sgca−/− (LGMD2D) | rAAV2/1mSeAP-propmyoD76A | Increased muscle mass in calpain-3-null mice, no effect in Sgca−/−-mice | EDL: increased force (calpain-3-null mice) | EDL: No effect (calpain-3-null mice) |
Soleus: Increased force (calpain-3-null mice) |
Soleus: No effect (calpain-3-null mice) |
[86] | |||
| Soluble Receptor (sActRIIB-Fc) | ||||||||||
| Wild-type, C57BL/6 C57BL/10 |
ACE-031, sActRIIB, RAP-031 ACE-2494 |
Increased muscle weight. Fiber CSA increased in EDL [87] and in whole TA [88] |
Soleus: Type I and II-fiber CSA increased [89]. Quad; increased size of I, IIA, IIB-fibers. No fiber-type switch [90] |
EDL: twitch force increased, no effect on tetanic force [87]. Gas: no effect on max tetanic force [91] |
EDL: no effect [92,93] Gas: decreased [91] |
Soleus: increased force [92] | Soleus: no effect force [92] | [87,88,89,90,91,92,93,94,95,96] | ||
| Mouse/mdx | RAP-031, sActRIIB-Fc |
Muscle weight increased Diaphragm and triceps myofiber increased [97]. EDL single fiber CSA increased [98]. |
No fiber-type conversion [92] | EDL: increased force [98,99] | EDL: increased force [98], No effect [99]. EDL, TA decreased force in older animals |
Soleus decreased force | Soleus decreased force | No effect | Diaphragm, TA: No effect on histopathology, hydroxyproline [94,98]. Fibrosis decreased [97]. No visible effects on H/E pathology. SDH stains without effect of treatment [100]. eMHC: no effect [94]. |
[92,94,97,98,99,100] |
| Mouse/TgActa1H40Y, Mtm1R69C, Mtm1δ4, R6/2, Dysf−/−, Cav3P104L |
RAP-031, sActRIIB-Fc |
Increased muscle weight, increased fiber size | Quad: oxidative fiber diameter increased. Diaphragm: glycolytic myofibers hypertrophy [101]. IIB fiber hypertrophy, no fiber type switch [90,102] |
No effect [101]. EDL, TA increased force [103] |
No effect [101] | No effect [101] | No effect [101] | Nemaline rod structures unchanged [101]. Gross evaluation of diaphragm: unaffected by genotype or treatment [90]. Fibrotic changes improved |
[90,101,102,103,104,105] | |
| Anti-ActRIIB Antibody | ||||||||||
| Mouse/SCID | BYM338 | Increased weight of TA, EDL, Gas. Soleus increased weight (in high dose) [106] |
Gas: increased force [107] | [106,107] | ||||||
| Mouse/C57BL/6 (glucocorticoid-induced atrophy) | BYM338 | TA weight and CSA increased | TA increased force | [106] | ||||||
| Follistatin Administration or Overexpression | ||||||||||
| Mouse/ F66;Dysf−/−, F66;mdx |
Follistatin overexpression | Muscle mass maintained in F66;mdx, decreased in F66;Dysf−/− | F66;Dysf−/−: EDL: Decreased force |
F66;Dysf−/−: Exacerbation of dystrophic features. Increased Evans Blue Dye (EBD) uptake F66;mdx: Dystrophic features not exacerbated, mild improvement |
[104] | |||||
| Mouse/mdx, Sod1G93A | AAV-delivered follistatin i.m. | Increased weight of TA, Gas, Quad, triceps | Increased grip strength | Young mdx: increased myofiber size. Satellite cell markers: no diff Old mdx: Fever necrotic fibers and mononuclear infiltrates |
[108,109] | |||||
| Monkey/Cynomolgus | AAV-delivered follistatin i.m | Increased fiber size | Quad: Increased force | Myofiber hypertrophy | [110] | |||||
| Mouse/C57BL10, mdx, | ACE-083 | Increased CSA, weight | TA: increased force | TA: no effect | [111] | |||||
| Mouse/C57BL/6 | FS-EEE-mFc and FST288-Fc | Increased muscle weight | [99,112] | |||||||
| Mouse/mdx | FS-EEE-mFc | Increased weight in gas, Quad, triceps, TA | EDL: Increased force | EDL: No effect | Decreased necrosis and fibrosis in Quad, no effect in diaphragm | [99] | ||||
| Liver-mediated Overexpression of Dominant-negative Myostatin (dnMSTN), sActRIIB and Myostatin Propeptide | ||||||||||
| Mouse/MF-1 (wild-type) | AAV8 over-ekspression (propeptide) | Gas, TA increased mass. EDL and soleus increased CSA. | Increased CSA of type I, IIA and IIB-fibers | EDL: No effect | EDL: No effect | Soleus: increased force | Soleus: No effect | [113] | ||
| Mouse/SmaC/C | AAV-mediated systemic expression (dnMSTN and sActRIIB) | Increased weight in TA, Gas, Quad. dnMSTN-cohort: Increased CSA in EDL and TA but not in soleus |
TA: Increased IIA size EDL: Increased IIA and IIB size and total fiber number. Soleus: No effect vs. controls. I-fibers generally unaffected |
EDL increased vs. SMAC/C control | EDL; Decreased force | Soleus: Increased force | Soleus: No effect | [114] | ||
| Mouse/mdx | AAV-delivered liver-specific promoter: dnMSTN, sActRIIB | Increased weight in TA, Gas, Quad, EDL, Soleus EDL: increased CSA Soleus: No effect in weight [115] |
EDL: IA + IIB increased fiber size. Increased proportion of IIB fibers in EDL and Soleus. Soleus: Increased size and proportion of IIA-fibers Diaphragm: IIX fibers proportion increased, IIA fibers proportion decrease [116] Diaphragm: No effect in specific fiber-type size [115] |
EDL: increased force | No effect (decreased force by 10 months of treatment) | Soleus: increased force | Soleus increased force [116] Soleus no difference [115]. Diaphragm: no effect |
[115,116,117] | ||
| Dog/GRMD | AAV-delivered liver-specific promoter (dnMSTN) | Increased weight in Tibialis cranialis, EDL, Gas, flexor digitorum superficialis | Increased size of IIA-fibers, no effect in I-fibers. No fiber type switch |
[118] | ||||||
| RNA Interference and Anti-oligonucleotides against Myostatin or ActRIIB | ||||||||||
| Mouse/mdx | Antimyostatin PMO | No effect in weight of diaphragm, EDL, Gas, Soleus, TA | Diaphragm: no difference in fiber-type content (I, IIA, IIX, IIB) | Diaphragm and TA: no effect on fiber diameter and collagen IV content | [119] | |||||
| Mouse/mdx (female) | AAV-delivered shRNA, i.m. | TA: No effect on CSA, fiber number increased | TA: No effect | TA: No effect | [120] | |||||
| AAV-Cas9-mediated Myostatin Gene Editing | ||||||||||
| Mouse/C57/BL10 | rAAV-SaCas9 | Increased fiber area and number of fibers per area | [79] | |||||||
| Myostatin Knock-out/Crossbreeding | ||||||||||
| Mouse/Mstn−/− | Increased muscle weight vs. wild-type. Increased fiber number and CSA of EDL and soleus [121] |
EDL fiber-type composition: IIA and IIX incidence decreased, IIB increased in EDL and TA. Soleus CSA increased only in IIA-fibers [122] |
EDL: Increased [121]/no effect [122,123] |
EDL: Decreased |
Soleus: Increased | Soleus: No effect | EDL: Force deficit Soleus: No force deficit |
Decreased hydroxyproline content in EDL, no effect in soleus [121]. Cytoplasmic inclusions of tubular aggregates in older mice [123] |
[121,122,123,124,125,126,127] | |
| Mouse/BehC/C | Increased muscle weight | EDL: No effect [123] | EDL: Decreased force [123] | [123,128] | ||||||
| Mouse/ Mstn−/−;mdx Mstn−/−;Sgcd −/− MstnPro;Cav3P104L |
Increased mean fiber diameter and muscle weight [105,129,130] |
Mstn−/−;mdx: Reduced fibrosis [129] Mstn −/−;Sgcd −/−: Hydroxyproline content decreased in EDL [75] |
[75,105,129,130] | |||||||
| Mouse/Mstn−/−; dyW/dyW | Increased muscle mass, muscle CSA and fiber CSA. (increased mortality) |
Decreased type I fiber composition | No effect on necrosis, inflammation or infiltrating cells. Less fat tissue. | [131] | ||||||
Mainstream results from various antimyostatin treatments in animal models. Specific results that were distinct for a particular study and not general for all of the references have been titled as such. Abbreviations: AAV; adeno-associated virus, ActRIIB; activin receptor type IIB, CSA; cross-sectional area, EDL; m. extensor digitorum longus, eMHC; embryonic myosin heavy chain, Gas; m. gastrocnemius, GRMD; golden retriever muscular dystrophy i.m.; intra-muscular injection, LGMD; limb-girdle muscular dystrophy, Quad; m. quadriceps, SDH; succinate dehydrogenase, TA; m. tibialis anterior, TB; m. triceps brachii.