Combined Effects of Protein/Fat Deficiency and Disuse on Skeletal Muscle Mass and Function in Mice.

Abstract

<h4>Background</h4>Sarcopenia is driven by multifactorial insults, including undernutrition and disuse; however, the causal links between inadequate nutrition and the loss of muscle mass and strength remain unclear. This study aimed to establish mouse models of protein and/or fat deficiency and to investigate their interaction with disuse on skeletal muscle.<h4>Methods</h4>Nine-week-old male C57BL/6J mice fed isocaloric diets for 8 weeks: normal chow (NC), low fat (LF), low protein (LP), or low protein and low fat (LPLF). Outcomes included body weight, grip strength test, gastrocnemius and soleus muscle weights, cross-sectional area (CSA) of gastrocnemius muscle fibers, and gastrocnemius muscle mRNA expression of ubiquitin-proteasome system (UPS) markers (atrogin-1, MuRF1) and inflammatory cytokines (TNF-α, IL-6, IL-1β). After the 8-week diet phase, a disuse model using bilateral hindlimb immobilization for 1, 3, or 7 days was applied under continued isocaloric feeding to assess diet-disuse interactions.<h4>Results</h4>Compared with NC, the LF, LP, and LPLF groups showed reduced body weight, grip strength, muscle mass, and myofiber CSA. Upregulation of UPS-related genes was observed in LPLF, whereas the expression of inflammation-related genes did not differ from NC in LF, LP, and LPLF. When combined with immobilization, LP and LPLF diets further exacerbated the decreases in muscle mass and strength compared with NC, accompanied by increased expression of both UPS- and inflammation-related genes.<h4>Conclusions</h4>An animal model of diet-induced reduction in muscle mass and strength was established, which will be useful for investigating the effects of protein and fat deficiency on skeletal muscle. Elucidating the detailed molecular pathways involved remains an important goal for future research and may provide new insights into nutritional approaches to prevent or treat sarcopenia.