Evaluation of Electrical Impedance as a Biomarker of Myostatin Inhibition in Wild Type and Muscular Dystrophy Mice.
OBJECTIVE
Non-invasive and effort independent biomarkers are needed to better assess the effects of drug therapy on healthy muscle and that affected by muscular dystrophy (mdx). Here we evaluated the use of multi-frequency electrical impedance for this purpose with comparison to force and histological parameters.


METHODS
Eight wild-type (wt) and 10 mdx mice were treated weekly with RAP-031 activin type IIB receptor at a dose of 10 mg kg-1 twice weekly for 16 weeks; the investigators were blinded to treatment and disease status. At the completion of treatment, impedance measurements, in situ force measurements, and histology analyses were performed.


RESULTS
As compared to untreated animals, RAP-031 wt and mdx treated mice had greater body mass (18% and 17%, p < 0.001 respectively) and muscle mass (25% p < 0.05 and 22% p < 0.001, respectively). The Cole impedance parameters in treated wt mice, showed a 24% lower central frequency (p < 0.05) and 19% higher resistance ratio (p < 0.05); no significant differences were observed in the mdx mice. These differences were consistent with those seen in maximum isometric force, which was greater in the wt animals (p < 0.05 at > 70 Hz), but not in the mdx animals. In contrast, maximum force normalized by muscle mass was unchanged in the wt animals and lower in the mdx animals by 21% (p < 0.01). Similarly, myofiber size was only non-significantly higher in treated versus untreated animals (8% p = 0.44 and 12% p = 0.31 for wt and mdx animals, respectively).


CONCLUSIONS
Our findings demonstrate electrical impedance of muscle reproduce the functional and histological changes associated with myostatin pathway inhibition and do not reflect differences in muscle size or volume. This technique deserves further study in both animal and human therapeutic trials.
Department of Neurology, Division of Neuromuscular Diseases, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215-5491, United States of America.
Benjamin
B
Sanchez
Department of Neurology, Division of Neuromuscular Diseases, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215-5491, United States of America.
Jia
J
Li
Department of Neurology, Division of Neuromuscular Diseases, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215-5491, United States of America.
Sung
S
Yim
Department of Neurology, Division of Neuromuscular Diseases, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215-5491, United States of America.
Adam
A
Pacheck
Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02215-5491, United States of America.
Jeffrey J
JJ
Widrick
Department of Neurology, Division of Neuromuscular Diseases, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215-5491, United States of America.
Seward B
SB
Rutkove
D000818:Animals; D015415:Biomarkers; D017097:Electric Impedance; D051379:Mice; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000378:metabolism / Q000503:physiopathology*; D009137:Muscular Dystrophy, Animal / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D055435:Myostatin / Q000235:genetics / Q000378:metabolism*
D015415:Biomarkers; D055435:Myostatin