Fat-specific protein 27 (FSP27) is a critical determinant of intramuscular triglyceride storage and skeletal muscle function

Skeletal muscle relies on the rapid mobilization of lipid fuels to sustain endurance activity, yet the mechanisms that preserve this energy source remain incompletely understood. Here, we identify Fat-specific protein 27 (FSP27) as a critical regulator of muscle lipid availability, as its loss in mice leads to profound depletion of intramuscular lipid stores and impaired skeletal muscle endurance and strength. In our previous studies, despite elevated oxidative metabolism, global Fsp27-/- mice displayed severe decline in skeletal muscle endurance and strength, along with intramuscular triglyceride content by 10 months of age. We hypothesized that chronically elevated oxidative metabolism accelerates depletion of intramuscular lipid fuels, leading to reduced fuel availability, premature fatigue, and loss of muscle strength. To test this hypothesis, male and female Wild Type and Fsp27-/- mice were assessed for muscle endurance and strength at 6 and 2 months of age via a treadmill running endurance and four-limb hanging grid experiment, respectively. We found that intramuscular triglyceride stores were already markedly reduced by 2 months of age, indicating early-onset fuel limitation before cumulative metabolic stress could occur. Consistently, Fsp27-/- mice displayed significantly reduced endurance and strength at both ages, coinciding with markedly lower intramuscular triglyceride levels. Together, these findings demonstrate that early functional deficits in Fsp27-/- mice arise from impaired lipid fuel availability rather than increased oxidative metabolism. Our findings reveal FSP27 as a key molecular safeguard of intramuscular lipid stores, whose loss leads to lipid depletion and compromised muscle endurance and strength. Funding Sources: NIH/NIDDK grant RO1DK138635 (VP), RO1DK101711 (VP), RO1HL140836 (VP), and funds from Osteopathic Heritage Foundation’s Vision 2020. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.