Methods and compositions for improving exercise endurance, performance, or tolerance
Among the various aspects of the present disclosure is the provision of methods and compositions for improving exercise endurance, performance, or tolerance using an S1P inhibiting agent.
1. A method of improving exercise tolerance or enhancing exercise performance in a subject comprising:
administering a pharmaceutical composition comprising a S1P inhibiting agent in an amount effective to reduce or deplete S1P levels or reduce or deplete S1P activity in the subject and improve exercise tolerance or enhance exercise performance compared to the subject prior to being administered the pharmaceutical composition, wherein the subject has a mutation in a gene encoding S1P (MBTPS1) that results in an increase in S1P protein that is expressed or an increase in activity of S1P target pathways compared to a subject having wild type MBTPS1.
2. The method of claim 1 , wherein the mutation is a replacement of proline with serine in a transmembrane domain of S1P at a position corresponding to position 1003 of SEQ ID NO: 20, and the transmembrane domain of the mutant S1P comprises instant SEQ ID NO: 19.
3. A method of treating a disease, disorder, or condition associated with reduced exercise tolerance or endurance in a subject comprising
administering a pharmaceutical composition comprising a S1P inhibiting agent in an amount effective to reduce or deplete S1P levels or reduce or deplete S1P activity in the subject and improve exercise tolerance or enhance exercise performance compared to the subject prior to being administered the pharmaceutical composition, wherein the subject has a mutation in a gene encoding S1P (MBTPS1) that results in an increase in S1P protein that is expressed or an increase in activity of S1P target pathways compared to a normal subject having wild type MBTPS1.
4. The method of claim 3 , wherein, after being administered the pharmaceutical composition, the subject exhibits:
increased expression of genes encoding enzymes involved in fatty acid metabolism;
higher capacity for fatty acid oxidation;
enhanced mitochondrial metabolism;
reduced respiratory exchange ratio (RER) value;
increased long-chain fatty acid (LCFA) muscle uptake;
elevated markers of fatty acid oxidation; or
decreased serum triglyceride (TAG) levels;
optionally, in response to exercise stimulus,
compared to the subject prior to being administered the pharmaceutical composition.
5. The method of claim 3 , wherein the subject has a gain of function mutation or a missense mutation in a S1P transmembrane domain, wherein the gain of function mutation or the missense mutation is a replacement of proline with serine in a transmembrane domain of S1P at a position corresponding to position 1003 of SEQ ID NO: 20, and the transmembrane domain of the mutant S1P comprises instant SEQ ID NO: 19.
6. The method of claim 3 , wherein the subject has or is suspected of having obesity, type 2 diabetes (T2DM), heart failure (HF), cardiovascular disease (CVD), insulin resistance, hypertension, hyperCKemia, myoedema, rhabdomyolysis, idiopathic chronic muscle fatigue, cardiac abnormalities, or dysfunctional muscle or heart.
7. The method of claim 3 , wherein the subject has muscle fatigue, swelling, or myoedema during or after moderate physical activity compared to a subject having wild type MBTPS1.
8. The method of claim 3 , wherein the subject is a mammal selected from a human, horse, or dog.
9. The method of claim 3 , wherein the S1P inhibiting agent is a small molecule inhibitor of S1P or a genetic inhibitor selected from an shRNA, an siRNA, and an anti-sense oligonucleotide (ASO), wherein the genetic inhibitor targets S1P mRNA and reduces, eliminates, or inhibits expression or activity of S1P.
10. The method of claim 3 , wherein the S1P inhibiting agent is PF-429242:
11. The method of claim 1 , wherein the increase in activity of S1P target pathways is selected from enhanced activation of SREBP, enhanced activation of UPR, or enhanced activation of ATF6.
12. The method of claim 3 , wherein the increase in activity of S1 P target pathways is selected from enhanced activation of SREBP, enhanced activation of UPR, or enhanced activation of ATF6.