METHODS FOR TREATING METABOLIC DISEASES BY INHIBITING MYOSTATIN ACTIVATION

1 - 20 . (canceled)

21 . A method of treating a metabolic disease in a subject, comprising administering to the subject a pharmaceutical composition comprising a myostatin-selective inhibitor, wherein the pharmaceutical composition has been prepared by a process comprising screening for an antibody or an antigen-binding fragment thereof that selectively binds to myostatin and/or a protein complex comprising myostatin and is capable of decreasing expression of pyruvate dehydrogenase kinase 4 (PDK4) and increasing expression of pyruvate dehydrogenase phosphatase 1 (PDP1) after administration.

22 . The method of claim 21 , wherein the pharmaceutical composition is administered in conjunction with a calorie restricted diet.

23 . The method of claim 21 , wherein the preparation of the pharmaceutical composition comprises culturing a host cell comprising one or more polynucleotides encoding the antibody or antigen-binding fragment under conditions that allow for expression of the antibody or antigen-binding fragment.

24 . The method of claim 21 , wherein the preparation of the pharmaceutical composition comprises purifying the antibody or antigen-binding fragment from the culture.

25 . The method of claim 21 , wherein the preparation of the pharmaceutical composition comprises formulating the antibody or antigen-binding fragment into a pharmaceutical composition suitable for administration to the subject, wherein the composition further comprises a pharmaceutically acceptable carrier or excipient.

26 . The method of claim 21 , wherein the myostatin-selective inhibitor is administered in an amount effective to decrease expression of PDK4 and increase expression of PDP1 in the subject.

27 . The method of claim 21 , wherein the metabolic disease is or comprises insulin resistance, inflammation, abnormal lipid metabolism, and/or an increase in intramuscular fat infiltration.

28 . The method of claim 21 , wherein metabolic disease is obesity, metabolic syndrome, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), and/or diabetes.

29 . The method of claim 28 , wherein the obesity is diet-induced obesity, obesity associated with type II diabetes, or sarcopenic obesity.

30 . The method of claim 28 , wherein the diabetes is type I diabetes or type II diabetes.

31 . The method of claim 21 , wherein the myostatin-selective inhibitor is engineered to bind FcRn with greater affinity at pH 7.4 relative to a non-engineered counterpart.

32 . The method of claim 21 , wherein the myostatin-selective inhibitor is administered subcutaneously.

33 . The method of claim 21 , wherein the host cells are CHO cells, 293 cells, or NS0 cells.

34 . The method of claim 21 , wherein the myostatin-selective inhibitor is an antibody or antigen-binding fragment that has been screened for the ability to bind to mature myostatin, GDF11, and/or Activin A, wherein the antibody or antigen-binding fragment does not bind to mature myostatin, GDF11, or Activin A.

35 . The method of claim 21 , wherein the myostatin-selective inhibitor is an antibody or antigen-binding fragment that binds to pro/latent myostatin.

36 . The method of claim 21 , further comprising administering to the subject an insulin secretion-promoting agent.

37 . The method of claim 21 , wherein the subject is a human subject.

38 . The method of claim 21 , wherein the subject is on an exercise regimen.

39 . The method of claim 21 , wherein the subject is not on an exercise regimen and/or is physical activity-limited.

40 . The method of claim 21 , wherein myostatin-selective inhibitor is administered in an amount effective to:

(a) increase expression of SHARP1 in the subject;

(b) decrease expression of MYL2, MYL4, and/or TNNC1 in the subject; and/or,

(c) decrease expression of PGC1A, NOR1, UCP1, and/or NUR77 in the subject.

41 . The method of claim 21 , wherein the administration is sufficient to cause at least one of the following in the subject:

(a) increase in mass and/or function of a muscle tissue;

(b) increase in mass and/or function of a fast twitch muscle tissue;

(c) increase in mass and/or function of a slow twitch muscle tissue;

(d) increase in metabolic rate;

(e) increase in insulin sensitivity;

(f) increase in the level of brown adipose tissue;

(g) increase in the level of beige adipose tissue;

(h) decrease in the level of white adipose tissue;

(i) decrease in the level of visceral adipose tissue;

(j) decrease in the ratio of adipose-to-muscle tissue;

(k) increase in glucose uptake by a target tissue, wherein the target tissue is brown adipose tissue, beige adipose tissue, or muscle tissue;

(l) decrease in glucose uptake by a target tissue, wherein the target tissue is a white adipose tissue or a liver tissue;

(m) decrease in muscle catabolism of protein and/or muscle release of amino acids;

(n) increase in insulin dependent glycemic control;

(o) decrease in intramuscular fat infiltration;

(p) prevention of muscle loss or atrophy;

(q) increase in bone density or volume; and

(r) prevention or reduction of bone loss or fracture.