2. Academic Validation
  3. Sulfur Amino Acid Restriction Enhances Exercise Capacity in Mice by Boosting Fat Oxidation in Muscle

Sulfur Amino Acid Restriction Enhances Exercise Capacity in Mice by Boosting Fat Oxidation in Muscle

  • bioRxiv. 2024 Jul 1:2024.06.27.601041. doi: 10.1101/2024.06.27.601041.
Charlotte G Mann 1,  Michael R MacArthur 2 3 4,  Jing Zhang 1,  Songlin Gong 1,  Jenna E AbuSalim 3 4 5,  Craig J Hunter 2 3 4,  Wenyun Lu 2 3,  Thomas Agius 6,  Alban Longchamp 6 7 8,  Florent Allagnat 6,  Joshua Rabinowitz 2 3 4 5,  James R Mitchell 1 9,  Katrien De Bock 1,  Sarah J Mitchell 4
Affiliations

Affiliations

  • 1 Department of Health Sciences and Technology, ETH Zurich, Zurich 8092, Switzerland.
  • 2 Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.
  • 3 Lewis-Sigler Institute of Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.
  • 4 Ludwig Institute for Cancer Research, Princeton University, Princeton, NJ 08544, USA.
  • 5 Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
  • 6 Department of Vascular Surgery, Lausanne University Hospital (CHUV), Lausanne 1005, Switzerland.
  • 7 Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
  • 8 Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
  • 9 Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
PMID: 39005372 DOI: 10.1101/2024.06.27.601041
Abstract

Dietary restriction of the sulfur-containing Amino acids methionine and cysteine (SAAR) improves body composition, enhances Insulin sensitivity, and extends lifespan; benefits seen also with endurance exercise. Yet, the impact of SAAR on skeletal muscle remains largely unexplored. Here we demonstrate that one week of SAAR in sedentary, young, male mice increases endurance exercise capacity. Indirect calorimetry showed that SAAR increased lipid oxidation at rest and delayed the onset of carbohydrate utilization during exercise. Transcriptomic analysis revealed increased expression of genes involved in fatty acid catabolism especially in glycolytic muscle following SAAR. These findings were functionally supported by increased fatty acid circulatory turnover flux and muscle β-oxidation. Reducing lipid uptake from circulation through endothelial cell (EC)-specific CD36 deletion attenuated the running phenotype. Mechanistically, VEGF-signaling inhibition prevented exercise increases following SAAR, without affecting angiogenesis, implicating noncanonical VEGF signaling and EC CD36-dependent fatty acid transport in regulating exercise capacity by influencing muscle substrate availability.

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    99.94%, 酪氨酸激酶抑制剂
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